Cannula For Minimizing Dilution Of Dosing During Nitric Oxide Delivery

ABSTRACT

The present invention generally relates to, amongst other things, systems, devices, materials, and methods that can improve the accuracy and/or precision of nitric oxide therapy by, for example, reducing the dilution of inhaled nitric oxide (NO). As described herein, NO dilution can occur because of various factors. To reduce the dilution of an intended NO dose, various exemplary nasal cannulas, pneumatic configurations, methods of manufacturing, and methods of use, etc. are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation under 35 U.S.C. § 120 of U.S. patentapplication Ser. No. 15/412,348, filed Jan. 23, 2017, which is acontinuation under 35 U.S.C. § 120 of U.S. patent application Ser. No.14/312,003, filed Jun. 23, 2014, now U.S. Pat. No. 9,550,039, which is acontinuation under 35 U.S.C. § 120 of U.S. patent application Ser. No.14/096,629, filed Dec. 4, 2013, now U.S. Pat. No. 8,770,199, whichclaims, under 35 USC § 119(e), the benefit of U.S. ProvisionalApplication No. 61/733,134, filed Dec. 4, 2012, U.S. ProvisionalApplication No. 61/784,238, filed Mar. 14, 2013, and U.S. ProvisionalApplication No. 61/856,367, filed Jul. 19, 2013, the contents of each ofwhich are hereby incorporated by reference in their entireties.

TECHNICAL FIELD

The present invention generally relates to improving the accuracy and/orprecision of nitric oxide therapy, reducing the dilution of inhalednitric oxide, and/or ensuring mixing within the patient's nose.

BACKGROUND

Nitric oxide (NO) gas, when inhaled, dilates blood vessels in the lungs,improving oxygenation of the blood and reducing pulmonary hypertension.Because of this, some provide nitric oxide as a therapeutic gas in theinspiratory breathing gases for patients with pulmonary hypertension.

Typically, inhaled NO is delivered in a carrier gas from a high pressuresource (e.g., a pressurized cylinder) to the patient at, or near,ambient pressure by means of a respiratory tube for ICU ventilatorbound/dependent or anesthesia patients or a nasal cannula forspontaneously breathing patients. Delivering an accurate and consistentdose to the patient through a nasal cannula can be particularlychallenging when the flow rate is pulsatile, for example, becausedilution of the dose can occur.

Accordingly, a need exists for new methods and apparatuses forpreventing dilution of dosing within the delivery conduit of a nitricoxide delivery apparatus, as well as methods of manufacturing suchapparatuses.

SUMMARY

Aspects of the present invention relate to improved nasal cannulas thatminimize retrograde flow and/or permeation of oxygen, air, and/or othergases during NO therapy while allowing NO delivery to one or both naresof the nostril. Such cannulas can reduce dilution of the delivered doseby using cannula materials and/or coatings that limit oxygen diffusionthrough the cannula walls and/or utilize cannula configurations thatprevent mixing of co-delivered O2 and NO and/or reduce retrograde flowthrough the patient end of the cannula.

Aspects of the present invention also relate to methods of minimizingthe dilution of the NO dose. Other aspects of the present inventionpertain to methods of treatment utilizing these nasal cannulas and/ormethods of administration. Other aspects of the present invention relateto methods of manufacturing multi-lumen cannulas and their nosepieces.

In exemplary embodiments, a nasal cannula of the present invention canbe for delivering at least one therapeutic gas to a patient in needthereof. The nasal cannula can include a first lumen, a second lumen,and a third lumen. The nasal cannula can also include a cannulanosepiece. The first lumen can be capable of delivering a firsttherapeutic gas to a patient in need thereof, the second lumen can becapable of transmitting a pressure change to a pressure change sensorand/or breath sensor, the third lumen can be capable of delivering asecond therapeutic gas to the patient, and/or the cannula nosepiece caninclude separate flow paths to the patient for the first lumen, thesecond lumen, and the third lumen. The at least one therapeutic gas canbe nitric oxide.

In exemplary embodiments, a nasal cannula of the present invention canbe used for therapeutic gas delivered to a patient. The nasal cannulacan include a first lumen, a second lumen, and/or a third lumen. Thefirst lumen can be a first therapeutic gas lumen for delivering a firsttherapeutic gas to a patient, the second lumen can be a triggeringlumen, and the third lumen can be a second therapeutic gas lumen fordelivering a second therapeutic gas to the patient. Further, a cannulanosepiece can allow separate flow paths to the patient for the firsttherapeutic gas lumen, the triggering lumen, and/or the secondtherapeutic gas lumen.

In exemplary embodiments, the nasal cannula can reduce dilution of oneor more of the first and second therapeutic gases delivered to thepatient and/or can be configured to be placed in fluid communicationwith at least one system to deliver the first and/or second therapeuticgases to the patient. The nasal cannula can inhibit mixing of nitricoxide and oxygen and/or the nasal cannula can reduce delivery ofnitrogen dioxide to the patient.

In exemplary embodiments, one or more of the first and secondtherapeutic gases to the patient for treatment of pulmonaryhypertension. In exemplary embodiments, the nasal cannula can deliverthe first and/or second therapeutic gases to the patient for treatmentof pulmonary hypertension, pulmonary hypertension secondary to chronicobstructive pulmonary disease (COPD), pulmonary hypertension aspulmonary arterial hypertension (PAH), pulmonary hypertension secondaryto idiopathic pulmonary fibrosis (IPF), and/or pulmonary hypertensionsecondary to sarcoidosis. The first therapeutic gas and the secondtherapeutic gas can be different gases or the same gas. In exemplaryembodiments, the first therapeutic gas can be nitric oxide and thesecond therapeutic gas can be oxygen and/or the first therapeutic gaslumen for delivering nitric oxide can be smaller than the secondtherapeutic gas lumen for delivering oxygen and/or the triggering lumen.In exemplary embodiments, the first therapeutic gas lumen can be fordelivering nitric oxide and/or can be about six feet to about eight feetin length having an inner diameter of about 0.01 inches to about 0.10inches. In exemplary embodiments, the triggering lumen can be about sixfeet to about eight feet in length having an inner diameter of about0.05 inches to about 0.20 inches.

In exemplary embodiments, the first therapeutic gas can be nitric oxideand/or the cannula nosepiece can include a nitric oxide flow path thatcan have an inner diameter that may be smaller than an inner diameter ofthe first therapeutic gas lumen. In exemplary embodiments, the firsttherapeutic gas can be nitric oxide and/or the cannula nosepiece caninclude a nitric oxide flow path having a volume that may be less thanabout 10% of a minimum pulse volume of the pulse of nitric oxide. Thecannula can include a wall material having a low oxygen transmissionrate that can be between

$0.001\frac{\left( {cm}^{3} \right)({mil})}{\left( {24\mspace{14mu} {hrs}} \right)\left( {100\mspace{14mu} {in}^{2}} \right)({ATM})}\mspace{14mu} {and}\mspace{14mu} 10{\frac{\left( {cm}^{3} \right)({mil})}{\left( {24\mspace{14mu} {hrs}} \right)\left( {100\mspace{14mu} {in}^{2}} \right)({ATM})}.}$

In exemplary embodiments, the cannula can further include a fourth lumenthat can be another first therapeutic gas lumen for delivering the firsttherapeutic gas to the patient. Further, the first lumen can deliver thefirst therapeutic gas to one nostril of the patient and the fourth lumencan deliver the first therapeutic gas to another nostril of the patient.In exemplary embodiments, the cannula can include at least one checkvalve in fluid communication with the first therapeutic gas lumen, acannula key, a scavenging material, and/or a flexible support bridgethat cushions the patient's nasal septum.

In exemplar embodiments, a nasal cannula of the present invention can beused for therapeutic gas delivered to a patient. The nasal cannula caninclude a first lumen, a second lumen, and a third lumen. The firstlumen can be a first therapeutic gas lumen for delivering a firsttherapeutic gas to a patient, the second lumen can be a triggeringlumen, and/or the third lumen can be a second therapeutic gas lumen fordelivering a second therapeutic gas to the patient. The firsttherapeutic gas lumen, the triggering lumen, and the second therapeuticgas lumen can aggregate at a cannula nosepiece. The cannula nosepiececan allow separate flow paths to the patient for the first therapeuticgas lumen, the triggering lumen, and/or the second therapeutic gaslumen. The first therapeutic gas lumen can have an inner diameter thatcan be smaller than an inner diameter of the second therapeutic gaslumen and an inner diameter of the triggering lumen and/or the firsttherapeutic gas lumen can have an inner diameter that can larger than aninner diameter of the flow path for the first therapeutic gas lumen atthe cannula nosepiece.

In exemplary embodiments, the nasal cannula can reduce dilution of thefirst and/or second therapeutic gases delivered to the patient and/orcan be configured to be placed in fluid communication with at least onesystem to deliver the first and/or second therapeutic gases to thepatient. The nasal cannula can inhibit mixing of nitric oxide and oxygenand/or the nasal cannula can reduce delivery of nitrogen dioxide to thepatient.

In exemplary embodiments, one or more of the first and secondtherapeutic gases to the patient for treatment of pulmonaryhypertension. In exemplary embodiments, the nasal cannula can deliverthe first and/or second therapeutic gases to the patient for treatmentof pulmonary hypertension, pulmonary hypertension secondary to chronicobstructive pulmonary disease (COPD), pulmonary hypertension aspulmonary arterial hypertension (PAH), pulmonary hypertension secondaryto idiopathic pulmonary fibrosis (IPF), and/or pulmonary hypertensionsecondary to sarcoidosis. In exemplary embodiments, the firsttherapeutic gas lumen can be for delivering nitric oxide and can beabout six feet to about eight feet in length having an inner diameter ofabout 0.01 inches to about 0.10 inches. The triggering lumen can beabout six feet to about eight feet in length having an inner diameter ofabout 0.05 inches to about 0.20 inches.

In exemplary embodiments, the first therapeutic gas can be nitric oxideand the cannula nosepiece can include a nitric oxide flow path having avolume that can be less than about 10% of a minimum pulse volume of thepulse of nitric oxide. The cannula can include a wall material having alow oxygen transmission rate that can be between

$0.001\frac{\left( {cm}^{3} \right)({mil})}{\left( {24\mspace{14mu} {hrs}} \right)\left( {100\mspace{14mu} {in}^{2}} \right)({ATM})}\mspace{14mu} {and}\mspace{14mu} 10{\frac{\left( {cm}^{3} \right)({mil})}{\left( {24\mspace{14mu} {hrs}} \right)\left( {100\mspace{14mu} {in}^{2}} \right)({ATM})}.}$

In exemplary embodiments, the cannula can include at least one checkvalve in fluid communication with the first therapeutic gas lumen, acannula key, a scavenging material, and/or a flexible support bridgethat cushions the patient's nasal septum.

In exemplar embodiments, a nasal cannula of the present invention can beused for therapeutic gas delivered to a patient. The nasal cannula caninclude a first lumen, a second lumen, and a third lumen. The firstlumen can be a first therapeutic gas lumen for delivering nitric oxidegas to a patient, the second lumen can be a triggering lumen, and thethird lumen can be a second therapeutic gas lumen for delivering one ormore of oxygen gas and air gas to the patient. The first therapeutic gaslumen, the triggering lumen, and/or the second therapeutic gas lumen canaggregate at a cannula nosepiece, the cannula nosepiece can allowseparate flow paths to the patient for the first therapeutic gas lumen,the triggering lumen, and/or the second therapeutic gas lumen. The flowpath for the first therapeutic gas lumen for delivering nitric oxide tothe patient can have a volume at the cannula nosepiece that can be lessthan about 10% of a minimum pulse volume of the pulse of nitric oxide.The first therapeutic gas lumen can have an inner diameter that can besmaller than an inner diameter of the second therapeutic gas lumen andan inner diameter of the triggering lumen and/or the first therapeuticgas lumen can have an inner diameter that can be larger than an innerdiameter of the flow path for the first therapeutic gas lumen at thecannula nosepiece.

In exemplar embodiments, a method for treating pulmonary hypertensioncan include administering nitric oxide gas to a patient in need thereof,wherein the nitric oxide can be administered through a nasal cannula,wherein the nasal cannula can include a first lumen, a second lumen, anda third lumen. In exemplary embodiments, nitric oxide is for treatmentof pulmonary hypertension. In exemplary embodiments, the nasal cannulacan deliver nitric oxide to the patient for treatment of pulmonaryhypertension, pulmonary hypertension secondary to chronic obstructivepulmonary disease (COPD), pulmonary hypertension as pulmonary arterialhypertension (PAH), pulmonary hypertension secondary to idiopathicpulmonary fibrosis (IPF), and/or pulmonary hypertension secondary tosarcoidosis.

In exemplar embodiments, the nitric oxide can be pulsed early ininspiration and/or delivered in the first half of inspiration. Inexemplar embodiments, the nitric oxide can be administered by pulsedinhalation to spontaneously breathing patients, the nitric oxide can beadministered at the onset of inspiration, the dose of nitric oxide canbe about 0.010 mg/kg/hr, and/or the dose can be administered at theonset of inspiration over a pulse width of less than 260 milliseconds.In exemplar embodiments, the method can further comprise administeringoxygen to the patient.

In exemplar embodiments, a method of administering nitric oxide of thepresent invention can be used for treating pulmonary hypertension. Themethod can include administering nitric oxide gas to a patient, whereinnitric oxide can be administered through a nasal cannula. The nasalcannula can include a first lumen, a second lumen, and a third lumen.The first lumen can be a first therapeutic gas lumen for delivering anitric oxide gas to a patient, the second lumen can be a triggeringlumen, and the third lumen can be a second therapeutic gas lumen fordelivering oxygen gas to the patient. Further, a cannula nosepiece canallow separate flow paths to the patient for the first therapeutic gaslumen, the triggering lumen, and/or the second therapeutic gas lumen.The second lumen can be for sensing the onset of inspiration and/or achange in pressure.

In exemplary embodiments, the nasal cannula can reduce dilution of oneor more of the first and second therapeutic gases delivered to thepatient and/or can be configured to be placed in fluid communicationwith at least one system to deliver the first and/or second therapeuticgases to the patient. The first therapeutic gas lumen for deliveringnitric oxide can be smaller than both of the second therapeutic gaslumen for delivering oxygen and the triggering lumen. The firsttherapeutic gas lumen can have an inner diameter dimension that can beselected to be substantially small to reduce nitric oxide dilution byreducing transit time of NO through the cannula while also beingsubstantially large enough to not cause significant backpressure and notsubstantially distort nitric oxide pulses and/or the triggering lumencan have an inner diameter dimension that can be selected to besubstantially small while also can be substantially large enough toreduce delay and distortion of pressure signals. The cannula nosepiececan include a nitric oxide flow path that can have an inner diameterthat can be smaller than an inner diameter dimension of the firsttherapeutic gas lumen.

In exemplary embodiments, the cannula can include at least one checkvalve in fluid communication with the first therapeutic gas lumen, acannula key, a scavenging material, and/or a flexible support bridgethat cushions the patient's nasal septum. The cannula can include a wallmaterial having a low oxygen transmission rate that can be between

$0.001\frac{\left( {cm}^{3} \right)({mil})}{\left( {24\mspace{14mu} {hrs}} \right)\left( {100\mspace{14mu} {in}^{2}} \right)({ATM})}\mspace{14mu} {and}\mspace{14mu} 10{\frac{\left( {cm}^{3} \right)({mil})}{\left( {24\mspace{14mu} {hrs}} \right)\left( {100\mspace{14mu} {in}^{2}} \right)({ATM})}.}$

In exemplary embodiments, the cannula can further include a fourth lumenthat can be another first therapeutic gas lumen for delivering the firsttherapeutic gas to the patient. Further, the first lumen can deliver thefirst therapeutic gas to one nostril of the patient and the fourth lumencan deliver the first therapeutic gas to another nostril of the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

The features and advantages of various embodiments of the presentinvention will be more fully understood with reference to the following,detailed description when taken in conjunction with the accompanyingfigures, wherein:

FIG. 1, shows an exemplary nasal cannula, in accordance with exemplaryembodiments of the present invention;

FIG. 2A shows an exemplary flow directionality of NO gas during deliveryto patients, in accordance with exemplary embodiments of the presentinvention;

FIG. 2B shows an exemplary retrograde flow path, in accordance withexemplary embodiments of the present invention;

FIGS. 3A and 3B, show an exemplary mono-lumen cannula, in accordancewith exemplary embodiments of the present invention;

FIGS. 4 and 5A show an exemplary dual lumen cannula and/or exemplarypneumatic paths for the NO, oxygen, and trigger lumens, in accordancewith exemplary embodiments of the present invention;

FIG. 5B shows an exemplary cannula nosepiece of a dual-lumen cannulaand/or pneumatic paths, in accordance with exemplary embodiments of thepresent invention;

FIGS. 6A and 6B show exemplary pneumatic paths for the NO, oxygen, andtrigger lumens in a tri-lumen cannula, in accordance with exemplaryembodiments of the present invention;

FIGS. 6C and 7 show exemplary cannula nosepieces of a tri-lumen cannulaand/or pneumatic paths, in accordance with exemplary embodiments of thepresent invention;

FIGS. 8A and 8B show exemplary pneumatic paths for the NO, oxygen andtrigger lumens in a quad-lumen cannula, in accordance with exemplaryembodiments of the present invention;

FIGS. 8C and 8D show exemplary cannula nosepieces of a quad-lumencannula and/or pneumatic paths, in accordance with exemplary embodimentsof the present invention;

FIG. 9A shows an exemplary duck bill check valve, in accordance withexemplary embodiments of the present invention;

FIGS. 9B and 9C show exemplary umbrella and/or flapper check valves, inaccordance with exemplary embodiments of the present invention;

FIG. 10 shows an exemplary nasal cannula with an umbrella or flappervalve for delivering NO, in accordance with exemplary embodiments of thepresent invention;

FIGS. 11A and 11B show exemplary valves incorporated into the NOdelivery line, in accordance with exemplary embodiments of the presentinvention;

FIG. 12 shows exemplary flow from a blocked nostril to the patient'sother nostril, in accordance with exemplary embodiments of the presentinvention;

FIG. 13 shows injection of NO into a flow of ambient air into eachnostril, in accordance with exemplary embodiments of the presentinvention;

FIGS. 14A-14B show exemplary configurations of dual channel deliverysystems, in accordance with exemplary embodiments of the presentinvention;

FIG. 15 shows exemplary device components for exemplary embodiments of adual channel delivery system, in accordance with exemplary embodimentsof the present invention;

FIG. 16 shows an exemplary nasal cannula with a tri-lumen nosepiece, inaccordance with exemplary embodiments of the present invention;

FIG. 17 shows an exemplary tri-lumen nosepiece prior to assembly, inaccordance with exemplary embodiments of the present invention;

FIG. 18 shows an exemplary nasal prong of the assembled molded tri-lumennosepiece, in accordance with exemplary embodiments of the presentinvention;

FIGS. 19A-19B shows a perspective and a two-dimensional representationof an exemplary nasal prong with a NO lumen proximal to and within atrigger lumen, in accordance with exemplary embodiments of the presentinvention;

FIG. 20 shows an exemplary nasal cannula, in accordance with exemplaryembodiments of the present invention;

FIG. 21A shows an exemplary dual “D” shaped paratube, in accordance withexemplary embodiments of the present invention;

FIGS. 21B and 21C show exemplary lumina having geometric protrusionsand/or inserts, in accordance with exemplary embodiments of the presentinvention;

FIGS. 22A-22E views of exemplary nasal cannula device connection pieces,in accordance with exemplary embodiments of the present invention;

FIG. 23 shows an exemplary oxygen connection piece, in accordance withexemplary embodiments of the present invention;

FIG. 24 shows an exemplary reducer and/or additional line holder, inaccordance with exemplary embodiments of the present invention;

FIGS. 25A-C show various views of an exemplary cannula nosepiece, inaccordance with exemplary embodiments of the present invention;

FIG. 25D shows a front top right perspective view of an exemplarycannula nosepiece, in accordance with exemplary embodiments of thepresent invention;

FIG. 25E shows a bottom view of an exemplary cannula nosepiece, inaccordance with exemplary embodiments of the present invention;

FIG. 25F shows a top view of an exemplary cannula nosepiece, inaccordance with exemplary embodiments of the present invention;

FIG. 25G shows a first side view of an exemplary cannula nosepiece, inaccordance with exemplary embodiments of the present invention;

FIG. 25H shows a second side view of an exemplary cannula nosepiece, inaccordance with exemplary embodiments of the present invention;

FIG. 25I shows a front view of an exemplary cannula nosepiece, inaccordance with exemplary embodiments of the present invention;

FIG. 25J shows a back view of an exemplary cannula nosepiece, inaccordance with exemplary embodiments of the present invention;

FIG. 25K shows a front top right perspective view of an exemplarycannula nosepiece, in accordance with exemplary embodiments of thepresent invention;

FIG. 25L shows a bottom view of an exemplary cannula nosepiece, inaccordance with exemplary embodiments of the present invention;

FIG. 25M shows a top view of an exemplary cannula nosepiece, inaccordance with exemplary embodiments of the present invention;

FIG. 25N shows a first side view of an exemplary cannula nosepiece, inaccordance with exemplary embodiments of the present invention;

FIG. 25O shows a second side view of an exemplary cannula nosepiece, inaccordance with exemplary embodiments of the present invention;

FIG. 25P shows a front view of an exemplary cannula nosepiece, inaccordance with exemplary embodiments of the present invention;

FIG. 25Q shows a back view of an exemplary cannula nosepiece, inaccordance with exemplary embodiments of the present invention;

FIGS. 26A-26D show cross-sectional views of various exemplary cannulanosepiece nares, in accordance with exemplary embodiments of the presentinvention;

FIG. 27 show exemplary keying elements, in accordance with exemplaryembodiments of the present invention;

FIG. 28 shows an exemplary NO delivery device with a key slot and anasal cannula with a keying element, in accordance with exemplaryembodiments of the present invention;

FIG. 29 illustratively depicts exemplary retrograde flows duringinspiratory breathing along with pulsed delivery, in accordance withexemplary embodiments of the present invention;

FIG. 30 illustratively depicts exemplary retrograde flows during bothinspiratory and expiratory breathing, in accordance with exemplaryembodiments of the present invention;

FIG. 31 illustratively depicts exemplary retrograde flows for variousexemplary cannula configurations, in accordance with exemplaryembodiments of the present invention;

FIGS. 32A-32C show exemplary cannula configurations for Tests 1-3 ofFIG. 31, in accordance with exemplary embodiments of the presentinvention;

FIG. 33A shows a front top right perspective view of an exemplarytherapeutic gas delivery device, in accordance with exemplaryembodiments of the present invention;

FIG. 33B shows a front view of an exemplary therapeutic gas deliverydevice, in accordance with exemplary embodiments of the presentinvention;

FIG. 33C shows a back view of an exemplary therapeutic gas deliverydevice, in accordance with exemplary embodiments of the presentinvention;

FIG. 33D shows a first side view of an exemplary therapeutic gasdelivery device, in accordance with exemplary embodiments of the presentinvention;

FIG. 33E shows a second side view of an exemplary therapeutic gasdelivery device, in accordance with exemplary embodiments of the presentinvention;

FIG. 33F shows a top view of an exemplary therapeutic gas deliverydevice, in accordance with exemplary embodiments of the presentinvention;

FIG. 33G shows a bottom view of an exemplary therapeutic gas deliverydevice, in accordance with exemplary embodiments of the presentinvention;

FIG. 34A shows a top left back perspective view of another exemplarytherapeutic gas delivery device, in accordance with exemplaryembodiments of the present invention;

FIG. 34B shows a front top right perspective view of another exemplarytherapeutic gas delivery device, in accordance with exemplaryembodiments of the present invention;

FIG. 34C shows a top view of another exemplary therapeutic gas deliverydevice, in accordance with exemplary embodiments of the presentinvention;

FIG. 34D shows a bottom view of another exemplary therapeutic gasdelivery device, in accordance with exemplary embodiments of the presentinvention;

FIG. 34E shows a front view of another exemplary therapeutic gasdelivery device, in accordance with exemplary embodiments of the presentinvention;

FIG. 34F shows a back view of another exemplary therapeutic gas deliverydevice, in accordance with exemplary embodiments of the presentinvention;

FIG. 34G shows a first side view of another exemplary therapeutic gasdelivery device; in accordance with exemplary embodiments of the presentinvention; and

FIG. 34H shows a second side view of another exemplary therapeutic gasdelivery device, in accordance with exemplary embodiments of the presentinvention.

DETAILED DESCRIPTION

The present invention generally relates to, amongst other things,systems, devices, materials, and methods that can improve the accuracyand/or precision of nitric oxide therapy by, for example, reducing thedilution of inhaled therapeutic gases such as nitric oxide (NO) and/orlimiting mixing of the inhaled therapeutic gases prior to delivery intothe patient's nose. As described herein, NO dilution can occur becauseof various factors such as, but not limited to, NO mixing with oxygenand/or air. To reduce the dilution of an intended NO dose, variousexemplary nasal cannulas, pneumatic configurations, methods ofmanufacturing, and methods of use, etc. are disclosed. For example, thevarious exemplary nasal cannulas, pneumatic configurations, methods ofmanufacturing, and methods of use, etc. of the present invention canreduce mixing of NO with oxygen and/or air (e.g., prior to beingdelivered into the patient's nose, etc.) thereby reducing dilution ofintended NO doses.

Due to the unique nature of NO delivery, many factors need to beconsidered to ensure accurate and precise delivery of doses of NO to thepatient. Unlike the administration of other gases, such as oxygen (O2),NO dosing can be particularly susceptible to dilution because, amongstother things, the dose volume may be less than 1 ml (e.g. asubstantially small dose that can be lost to ambient) and/or NO can bereactive with O2 present in ambient air and/or co-administered O2producing nitrogen dioxide (NO2). Further, the timing of NO delivery canalso be more critical (e.g., for efficacy) than the timing of othergases (e.g., O2 delivery), so a need exists to reduce NO dilution andensure that the beginning of a patient's breath can be accuratelydetermined as soon as possible and/or to ensure that the NO dosewaveform does not significantly distort while traveling through thenasal cannula from the NO delivery device to the patient. Further,patient comfort may need to be factored into the design of the nasalcannula, for example, because the nasal cannula may be used forprolonged periods of time.

Various cannulas, systems, and methods of the present invention can use,modify, and/or be affiliated with various systems for deliveringpharmaceutical gas to a patient and/or for delivering a pulse ofpharmaceutical gas to a patient. For example, the various cannulas,systems, and methods of the present invention can use, modify, and/or beaffiliated with at least the therapeutic gas delivery systemsillustratively depicted in FIGS. 33A-34H. The various cannulas, systems,and methods of the present disclosure can use, modify, and/or beaffiliated with the teachings of U.S. Pat. No. 7,523,752 entitled“System and Method of Administering a Pharmaceutical Gas To a Patient”,the content of which is incorporated herein by reference in itsentirety.

Referring to FIG. 1, typically, using a delivery system 100 NO can bedelivered to a patient via a nasal cannula 101. Nasal cannula 101 canreceive NO at relatively low volumetric percent concentrations in acarrier gas from, for example, a therapeutic gas (e.g., NO) deliverydevice 103 and/or nasal cannula 101 can receive oxygen and/or ambientair (at times referred to simply as oxygen, O2, etc.) from anoxygen/ambient air supply 105. A commonly used carrier gas is nitrogenbecause nitrogen is non-reactive with NO, but other inert carrier gasessuch as helium can be used.

Delivery of the NO/N₂ gas mixture (at times referred to simply as nitricoxide, NO, etc.) to the patient typically requires that the NO gastravel from a high pressure NO source (e.g., a pressurized cylinder,pressurized cylinder affiliated with NO delivery device 103, etc.) tothe patient at, or near, ambient pressure, for example, via a deliverytube for ICU ventilator bound/dependent and/or anesthesia patientsand/or via a nasal cannula for spontaneously breathing patients. It willbe understood that various techniques and/or embodiments of theinvention disclosed herein can be used for a delivery tube and/or anasal cannula as well as other like apparatuses such as nasal pillowsand/or nasal masks, to name a few. For ease, at times only a cannula isshown and/or described. This is merely for ease and is in no way meantto be a limitation.

This above described transit of the NO, ideally, will be devoid ofcontact with other gasses, such as ambient air, oxygen, carbon dioxide,etc., until the gas enters the patient's upper respiratory tract.However, in practice, this may not be easily achieved. By way ofexample, oxygen and/or ambient air can enter delivery system 100 at anumber of points such as, but not limited to:

-   -   During the transit time within delivery device 103 (e.g., due to        oxygen diffusion through pneumatic interfaces such as        elastomeric O-rings into the inner pneumatics of the delivery        device, etc.);    -   During the NO gas transit through nasal cannula 101 (e.g., by        way of diffusion across the cannula wall, nosepiece, connectors,        reducer, bond joints, etc.);    -   During the inhalation/exhalation cycle when a driving pressure        gradient can reverse flow in the nasal cannula NO supply lumen        producing mixing within nasal cannula 101 with ambient air        and/or exhaled gas;    -   During the inhalation/exhalation cycle when NO and Air/O2 get        mixed in the patient nares;    -   During the connection of the high pressure source (e.g., a        pressurized cylinder, etc.) to the delivery device (e.g., as        cylinder replacement can trap small amounts of gas in the        delivery pneumatics, etc.); and    -   During the manufacturing cylinder filling operation of the high        pressure NO source in which a substantially pure mixture of NO        and carrier gas can be sought, but may not be easily achieved.

The dilution of NO during pulsed NO therapy can be problematic becauseonly a substantially small volume of NO may be delivered to the patient.For example, the NO-containing gas can be administered in pulses thatmay be less than one (1) milliliter (ml). With substantially small pulsevolumes, even small volumes of retrograde flow and/or diffused gases canbe significant, for example, because the small NO dose may be easilydiluted. Of course larger volumes of NO can also be diluted.

Minimization of NO/O2 Contact Due to O2 Diffusion Minimization of NOTransit Time

One or more embodiments of the present invention relate to nasalcannulas that address sources of NO/O2 contact (e.g., one or more of theabove sources of NO/O2 contact) and thereby dilution (e.g., by mixing ofNO with O2, etc.) of the intended NO dose by minimizing NO contact timewith O2, via minimizing transit time through the cannula, minimizing thetransit of oxygen across the cannula walls, and/or minimizing the amountof O2 coming in contact with NO. Referring to FIG. 1, addressing atleast dilution of intended NO doses, described below in greater detail,oxygen transit can be minimized across any lumina wall of cannula 101such as, but not limited to, cannula walls associated with a triggerlumen 104, NO lumen 106, O2/air lumen 108, and/or any combination and/orfurther separation thereof, to name a few. Also, addressing at leastdilution of intended NO doses, oxygen transit can be minimized acrossany wall of cannula 101, such as but not limited to, cannula wallsassociated with a cannula nosepiece 102, a keying member 110, reducer112, connection piece 114, oxygen connection piece 116, and/or anycombination and/or further separation thereof, to name a few.

Small ID NO Lumen

In one or more embodiments, cannulas can be provided that include asmaller inside diameter (ID) delivery tube/lumen for NO to, for example,reduce dilution of the intended NO doses. This smaller ID tube canreduce the transit time of the NO molecules through the cannula. This inturn can reduce the time available for mixing with oxygen which can bediffusing across the walls of the cannula and oxidizing the internal NOinto NO2.

By way of example, to reduce dilution of intended NO doses by minimizingNO transit time through the cannula, the ID for delivery tube/lumen forNO can be about 0.01 inches to about 0.10 inches and/or about 0.03inches to about 0.08 inches. In exemplary embodiments, the ID of thedelivery tube/lumen for NO can be selected to ensure reduced transittime of NO (e.g., reducing NO dilution, etc.) while not resulting insignificant backpressure and/or NO pulse shape distortion and/or NOwaveform distortion (discussed below in greater detail). To reducetransit time as well as not significantly cause backpressure and/ordistortion, the ID for delivery tube/lumen for NO may not besubstantially smaller than about 0.03 inches, for example, for a cannulahaving a length of about 6 feet to 8 feet. For shorter lengths a smallerID may be used and/or for longer lengths a larger ID may be used asresistance and/or distortion can be a function of both tube ID and tubelength.

In exemplary embodiments, the ID of shorter tubes/lumens for NO delivery(e.g. such as the cannula nares, shorter nasal cannulas, etc.) can havea substantially smaller tube ID than for delivery tubes/lumen for NO,which may also have a substantially small ID as described above, withoutsignificant backpressure and/or NO pulse shape and/or waveformdistortion occurring.

In exemplary embodiments, the potential for time of exposure of NO to O2can be minimized using other techniques such as, but not limited to,increasing the velocity of delivery of NO through the NO lumen. Thevelocity of NO through the NO lumen can be increased by, for example,increasing the pressure gradient within the system and/or by reducingthe diameter of the tube. Although the NO velocity can be increased toreduce the exposure time of NO to O2, the velocity can be required to beminimized so that the pulse shape is not substantially distorted, thepatient does not experience discomfort, and/or by factoring in any othercompeting metric.

It will be understood that the any of above teachings (e.g., small IDfor the delivery tube lumen for NO, etc.) can be combined with any ofthe other pneumatic configurations, cannula configurations, and/orteachings and/or embodiments described herein. For example, the aboveteachings (e.g., small ID for the delivery tube/lumen for NO, etc.) canbe used with the below described mono-lumen cannulas, dual-lumencannulas, tri-lumen cannulas, quad-lumen cannulas, and/or any otherteachings and/or embodiments described herein.

Materials to Limit Oxygen Diffusion and/or Remove O2 and/or NO2

Currently, many use polyvinyl chloride (PVC) and/or silicone as a commonmaterial for constructing nasal cannulas; however, oxygen can diffusethrough the lumen walls of these nasal cannulas. To minimize the oxygencontact occurring due to oxygen diffusion, permeation, and/ortransmission across the cannula's walls, cannula wall materials can beselected that minimize the oxygen diffusion rate, permeability rate,and/or oxygen transmission rate (OTR). In exemplary embodiments, thecannula wall can include a material with a low oxygen diffusioncoefficient, permeability rating, and/or oxygen transmission rate (OTR).By way of example, the cannula wall can include a material that can havean oxygen transmission rate (OTR) from about 0.001 to about 10, forexample, using the following units:

$\frac{\left( {cm}^{3} \right)({mil})}{\left( {24\mspace{14mu} {hrs}} \right)\left( {100\mspace{14mu} {in}^{2}} \right)({ATM})}$

-   -   where:    -   “cc” refers to the cubic centimeters (ml) of oxygen that crosses        a square of material;    -   “mil” refers to 1 mil (0.001″ thickness) of the square of        material;    -   “ATM” refers to the number of atmospheres of ambient pressure;    -   “24 hrs” refers to the duration allowed for oxygen flow; and    -   “100 in²” refers to the surface area of the square of material.

At times, when describing oxygen diffusion, permeation, and/ortransmission across the cannula's walls and/or cannula's materials,reference may only be made to at least one of diffusion rates, diffusioncoefficients, permeability rates, permeability ratings, and/or OTR. Itwill be understood that reference to any of the above terms, whenapplicable, can be used with and/or replaced by any of the above terms,and the like. For ease, at times only one and/or some of the above termsare described. This is merely for ease and is in no way meant to be alimitation.

In exemplary embodiments, cannula materials (e.g., material for thecannula tubing, the cannula nosepiece, etc.) can be adjusted and/orvaried to address O2 permeation along with patient comfort.

In exemplary embodiments, cannulas can be constructed using polyurethaneand/or similar soft material. In exemplary embodiments, the polyurethaneand/or similar soft material can include an additive to enhance theresistance to oxygen diffusion and/or tube coaxially located about atleast some of the cannula for NO delivery filled with a gas providingresistance to oxygen diffusion. The cannulas can be constructed bycoaxially coating a tube and/or co-extruding two or more materials(e.g., to form the tube, etc.). Of course other methods and/ortechniques for construction are within the scope of the disclosure.

Examples of at least some materials which can be used for constructionand/or that can have desired oxygen permeation properties include, butare not limited to, polymers such as polyvinylidene chloride (PVDC),ethylene vinyl alcohol (EVOH), polyamide (PA), polyvinylidene difluoride(PVDF), fluorinated polyurethane, Nylon 6, Nylon 12, and/or similarmaterials, to name a few. Further, PVC can be used as the cannulamaterial with one or more materials and/or additives, such as oxygenresistant polymers, incorporated to reduce the oxygen permeation,diffusion coefficient, and the like. Oxygen resistant polymers can beincorporated with the polyurethane, PVC, and/or other cannula materials,for example, through co-extrusion. By way of example, such an extrusioncan be achieved with co-extrusion dies and/or using other knowntechniques.

Tubing/lumen barriers to oxygen ingress can take one of a number ofpotential forms such as, but not limited to:

-   -   Homogenous and/or single material extrusions that can use at        least one material with low oxygen permeation characteristics;    -   Co-extrusions of two or more polymers, one or more of the        polymers having low oxygen permeation characteristics;    -   Surface treatment/surface coatings over materials/tubing with        such coatings can have low oxygen permeation characteristics;    -   Blends; and    -   Scavengers/getters/purifiers.

Homogenous and/or single material extrusions with low oxygenpermeability: In exemplary embodiments, materials such as polyvinylidinechloride (PVDC, trade name Saran®), ethylene vinyl alcohol (EVOH), Nylon6, Nylon 12, and/or any homogenous and/or single material extrusionswith low oxygen permeability can be used for the cannula material. Othermaterials are envisioned with these properties and the use of substitutelow oxygen permeation extrusion compatible material is within the scopeof this invention.

Co-extrusions of two or more polymers: In exemplary embodiments, atube-in-tube and/or multilayered sandwich configurations can beconstructed using co-extrusions of two or more polymers. For example,two or more polymers, with at least one having low oxygen permeationproperties, can be co-extruded (e.g., using common co-extrusion methodsknown in the art) to construct a tube-in-tube or multilayered sandwichconfiguration. The low oxygen permeation layer can include the polymersdisclosed herein (e.g., such as those listed in the previous section)and/or other polymers with similar characteristics. Since these polymersmay or may not co-extrude well with other polymers, it may be necessaryto extrude an intermediate or so called tie-layer polymer. Exemplaryco-extruded polymers can include, but are not limited to, PVC/EVOH/PVDC,PVC/EVOH/PFDF, fluorinated polyurethane/EVOH/PVDC and fluorinatedpolyurethane/EVOH/PVDF, PVC/PVDC, Polyurethane/PVDC, PVC/Nylon 6,PVC/Nylon 12, PVC/PVDC/Nylon 6, PVC/PVDC/Nylon 12,Polyurethane/PVDC/Nylon 6, Polyurethane/PVDC/Nylon12, tie layerpolymers, any combination and/or separation thereof, and/or any othermaterial that can be used with co-extrusions of two or more polymers.

In exemplary embodiments, co-extrusions can be layered in a specificorder, for example, to reduce oxygen permeation and/or diffusion and/orfor construction purposes. For example, if an adhesive used (e.g., inthe joining of components of the cannula, etc.) bonds PVC to PVC thenthe outer layer of a co-extrusion exposed to such adhesive can be PVC.Further, additional polymers (e.g., which may have reduced propertieswhen in contact with water vapor) such as, but not limited to, EVOH canbe sandwiched inside hydrophobic and/or water resistant outer and/orinner extrusion layers to minimize the contact of the internal compoundwith water vapor.

Surface treatment/surface coatings over tubing: In exemplaryembodiments, surface coatings (e.g., surface treatments, surfacecoatings, etc.) for low oxygen permeation can be applied to nasalcannula construction. Such coatings can include, but are not limited to,vacuum deposited silicon dioxide (silica) and/or aluminum (e.g., oxidesof aluminum, etc.) coatings heated above their sublimation temperaturethat can be deposited in thin layers a few microns (or less) thick. Forexample, silica coatings can be about 0.001 microns to about 10 micronsand/or about 0.01 microns to about 1 micron, and/or about 0.04 microns.

In exemplary embodiments, silica coatings can be deposited on plastic inlayers that can be substantially thin enough such that flexibility ofthe plastic may not be materially affected. It will be understood thatany reasonable technique can be used for deposition of such materials.For example, low cost deposition can be achieved using chemical vapordeposition treatment. Of course other deposition methods for thesecoatings can also be used such as, but not limited to, E-beam andThermal Evaporation, DC Magnetron Sputtering, Plasma-Assisted ReactiveSputtering, any combination and/or further separation thereof, and/orany technique capable of deposition.

In exemplary embodiments, other coatings such as, but not limited to,thermoset epoxy-amine coatings, epoxy-amine coatings, etc. can be used.Coatings can be applied and/or provided using techniques describedherein and/or known techniques.

Blends: In exemplary embodiments, materials can be blended together toobtain the beneficial properties of one or the other materials and/orused as the cannula material. In exemplary embodiments, Nylon 6 andEVOH, which can adhere to each other in co-extrusions without the needfor a tie layer, can be used as a blended cannula material. Other blendscan include, but are not limited to, Nylon 6 with amorphous nylon andNylon 6 with HDPE. Of course other blends can be used.

In exemplary embodiments, a later material can be coated over an earliermaterial. By way of example, when two materials are not compatible withco-extrusion due to different melt temperatures, one polymer can beextruded first and the second polymer can be heated and coated over thefirst in a secondary operation.

Scavengers/getters: In exemplary embodiments, scavengers can be coatedto the inside of the lumen (e.g., by baking off the liquid in a liquidsuspension of the scavenger to the inside of the lumen, by condensingout the scavenger on the inside of the lumen by evaporative processes,by absorbing/adsorbing to the inside surface of the lumen using a liquidor gaseous scavenger source, by chemically bonding the scavenger to theinside surface of the cannula, etc.) and/or the scavenger can bepackaged within the device connector and/or nosepiece, for example, as aplug (e.g., a plug with at least one hole to allow flow of gas throughit, etc.) to scavenge oxygen and/or nitrogen dioxide. Such scavengerscan include, but are not limited to, compounds such as activatedalumina, ascorbic acid, and/or any other scavenging compound. Potentialdrawbacks of such an approach include the finite lifespan of thescavenging material. This drawback can be overcome by factoring in useduration of the cannula into the design. At least one additionalpotential drawback can be that any plug configuration for gas transitthrough a scavenger may distort the gas waveform. In light of this plugsdescribed may be designed to minimize such waveform distortion. Anymethod can be used to coat the inside of the lumen. By of example, aliquid that is concentrated with a scavenger (e.g., ascorbic acid) canbe passed through the tube and then dried on such that it may then bedeposited on the inner wall of the tube.

In exemplary embodiments, activated alumina can be used in the cannula,for example, as a coating in the inside of the lumen, as a plug fitting,and/or used in any other way, for example, for the capture of nitrogendioxide. With a thin layer of alumina coated to the inside of the lumen,the effect can not only be a reduction of the oxygen permeation rate,but can also be successful for capture of nitrogen dioxide. Activatedalumina and/or other scavengers can also be made in the form of a plugfitted into the tube, for example, in an area close in proximity to thenostrils of the patient. The plug may be designed to minimize pressuredrop and/or to maintain the shape of nitric oxide pulse wave. The highsurface area of activated alumina can effectively scrub nitrogen dioxidefrom the gas mixture. Further, the scavenger can also be located in thedevice, for example, at the device connector. In this fashion, thescavenger can be part of the cannula and/or may be removable (e.g., suchthat it may be removed when changing the cannula) and/or the design lifeof the scavenger can be matched to anticipated and/or actual useduration of the cannula.

It will be understood that the invention is not limited to activatedalumina and that any material with a high surface area, substantialnitrogen dioxide scrubbing capability, proper pore sizes, enoughphysical strength so that the shape could be maintained, and/or that maynot generate powders and/or other materials that may shed or decouplefrom the cannula can act in the capacity of the scrubbing material. Itis further understood that internal filtering may be used to containshedding compounds to prevent aspiration in the respiratory system.Examples of scrubbing materials include, but are not limited to,zeolites, silica-alumina, activated carbon/coal, and adsorbents that canhave solid base sites on the surface. For ease, at times, activatedalumina is described as a scrubbing material. This is merely for easeand is in no way meant to be a limitation.

In exemplary embodiments, a reducing agent can be coated on the surfaceof the scrubbing material, for example, to enhance its ability tocapture and/or reduce nitrogen dioxide to nitric oxide. Such reducingagents include, but are not limited to, ascorbic acid.

In exemplary embodiments, additives can be added to the polymer tochange the permeation/barrier properties such as, but not limited to,oxidizable plastic (e.g. PET or polyamide), nanoclays, any combinationand/or further separation thereof, and/or any other additive. Additivescan work to scavenge the oxygen and/or provide a barrier to permeationwithin the polymer matrix, either of which can result in reduced oxygenpermeating through the material. Oxidizable plastics (e.g. PET orpolyamide) can react with the oxygen that may be permeating through thepolymer matrix. Oxygen that may be permeating through the membrane canreact with the oxidizable plastic prior to getting through the cannulaand/or reacting with NO. Nanoclays (e.g., that may tend to have a platelike morphology) can provide a barrier to permeation, for example, whenadequately dispersed within the polymer matrix. When dispersed,diffusion can be required to occur around the plates, which can resultin a tortuous path through the polymer thereby effectively reducing thegas permeability.

It will be understood that the any of above teachings (e.g., materials,etc.) can be combined with any of the other pneumatic configurations,cannula configurations, and/or teachings and/or embodiments describedherein. For example, the above teachings (e.g., materials, etc.) can beused with the below described mono-lumen cannulas, dual lumen cannulas,tri-lumen cannulas, quad lumen cannulas, and/or any other teachingsand/or embodiments described herein.

Configurations Retrograde Flow

Referring to FIGS. 2A-2B, it was surprisingly found that another sourceof dilution can be caused by a phenomenon (e.g., retrograde flow,cross-flow, etc.) in which ambient air and/or exhaled gas flows into thenasal cannula (e.g., at and/or near cannula nosepiece 200). This gasflow into the nasal cannula can be between two cannula nares (e.g.,cannula nares 202/203) displacing resident nitric oxide gas and/orpushing the nitric oxide gas out of the cannula so the displaced and/orpushed out nitric oxide may not be delivered to the patient and/or maymix with the gas flow and/or other gases, thereby diluting the intendedNO dose. Further, retrograde flow can depend on factors such as, but notlimited to, the pressure difference between the nares during bothinhalation and exhalation. The pressure difference between the nares canvary depending on factors such as, but not limited to, the person'sbreathing pattern, occlusions and/or partial occlusions in the person'snostrils (e.g., as shown in FIG. 12), placement of the nasal nares, andthe degree of misbalance between the nasal flow during breathing, toname a few. Accordingly, one or more embodiments of the presentinvention relate to nasal cannulas that can minimize the retrograde flowand/or dilution resulting from retrograde flow in the nasal cannula.

As shown in FIG. 2A, during normal pulsed delivery, NO flows out of bothnares 202/203 of cannula nosepiece 200. However, during at least thestatic phase between pulses, retrograde flow can occur. For example,during the static phase ambient or exhaled air can flow in a circularmotion and/or reversed flow in through one cannula nare 202 and out theother cannula nare 203 as shown in FIG. 2B. This retrograde flow canresult in dilution and/or washout of NO in the nasal nares and/or flowpath, which can cause a delay and/or reduction in the delivered dose.Furthermore, this retrograde flow can result in the oxygen in air and/orexhaled gas stream mixing with the NO to a greater degree and/orreacting with nitric oxide in the nasal cannula which may cause NO2formation that dilutes the NO concentration. Accordingly to reduceretrograde flow (e.g., that may result in NO2 formation that dilutes theNO doses and that can act as a known respiratory irritant, etc.), thevolume of potential nitric oxide mixing with either exhaled gas and/orambient gas may be minimized.

Noting the above, the amount of dilution resulting from retrograde flowcan be dependent on the volume of the lumen associated with NO delivery(e.g., the NO lumen; combined NO and triggering lumen; combined NO,triggering, and O2/air lumen; etc.) at the cannula nosepiece (e.g., flowpath) where retrograde flow may occur. The segment where retrograde flowmay occur can have any shape. For ease, this segment where retrogradeflow occurs is, at times, described as being “U” shaped, and the like.This is merely for ease and is in no way meant to be a limitation.

In exemplary embodiments, optimized ID dimensions (e.g., ID size, IDshape, etc.) of the lumen associated with NO delivery (e.g., the NOlumen; combined NO and triggering lumen; combined NO, triggering, andO2/air lumen; etc.) at the nosepiece (e.g., flow path) can be selectedto reduce the volume of the “U” shaped region thereby minimizing thepotential volumetric exchange associated with retrograde flow and/ordilution resulting from retrograde flow. Further, in exemplaryembodiments, such optimal ID dimensions can vary depending on the volumeof NO gas delivered. By way of example, a nitric oxide delivery devicecan deliver pulses of NO-containing gas with a minimum dose volume of0.35 ml. In order to ensure volumetric dosing accuracy, it may bepreferable that no more than a small percentage (e.g., 10%, 5%, 20%,etc.) of the dose can be lost due to retrograde flow.

One or more embodiments of the present invention limits the internalvolume of this “U” shape to be no more than a small percentage (e.g.,10%, 5%, 20%, etc.) of the minimum dose volume (e.g., 0.035 ml for a0.35 ml pulse of therapeutic gas) to ensure that if NO loss occurs it isan acceptable amount of NO loss due to retrograde flow (e.g., loss toambient during the exhalation phase). Following the above example, for a10% minimum dose volume of 0.035 ml, the lumen ID within the “U” segmentmay be no more than 0.046 inches given a prong length of 0.315 inchesand a prong spacing of 0.63 inches. Therefore, a lumen ID significantlylarger than 0.046 inches may not be advantageous to maintaining dosevolume accuracy for minimum dose volumes of 0.35 ml.

It will be understood that the mathematics of this construct can bemodified by variations in systems such as, but not limited to, systemswith larger or smaller minimum dose volumes appropriately, systems withdifferent prong lengths, and/or systems prong spacing, to name a few.One skilled in the art can perform the required calculations todetermine the ID required to provide a desired volume in the “U” shapedsegment so that it does not exceed 10% of the dose volume. Furthermore,depending on the required accuracy for the dosing, the internal “U”volume or other volume available for cross-flow can be, but is notlimited to, less than 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%,4%, 3%, 2% or 1% of the dose volume, to name a few.

For example, if the “U” shape consists of two nares and a backplane, themaximum dimensions such that the “U” volume does not exceed 20% of theminimum dose volume can be calculated using the following formula,wherein backplane refers to the length of the lumena inside thenosepiece and/or which forms the base of the “U” shape:

Minimum Dose Volume>5[2π(Prong Diameter/2)²*(Prong Length)+π(BackplaneDiameter/2)²*(Backplane Length)]

Thus, if the minimum dose is known, the dimensions of the cannula “U”section can be calculated. For dosing accuracies other than 20%, thevolume ratio factor of 5 can be changed accordingly with the volumeratio factor being equal to [100/(dose accuracy %)].

In exemplary embodiments, during exhalation and/or prior to inhalation(e.g., sensed and/or detected by the delivery device, etc.) the U-shapedvolume in the nosepiece can be purged with a pulse of NO substantiallyequal to the U-volume. This can cause the U-volume to be substantiallyfilled with NO (e.g., after exhalation). Further, this NO filling theU-volume can be delivered to the patient during the next inhalation, forexample, ensuring early delivery of NO to the patient to provide optimalclinical efficacy (e.g., discussed below).

In exemplary embodiments, retrograde flow can be reduced by at leastreducing the ID of the NO delivery lumen within the nasal prong (e.g.,NO flow path) so that the resistance to flow through the NO lumen at thenasal prong can be increased. Noting this configuration, under the samepressure differential, the flow within the NO lumen of the nasal prongscan be reduced as compared to prongs with larger lumen. This can resultin reduced cross flow under at least these conditions, for example,because the smaller ID NO lumen can produce gas flow resistance whichcan be inversely proportional to the fourth power of lumen's radius byPoiseuille's Law.

In exemplary embodiments, retrograde flow can be reduced by using valvesand/or check valves, for example, as discussed below in greater detail.

At times, the NO lumen described herein may be described as beingoptimized for a minimum pulse volume of 0.35 ml and/or allowed 10%dosing error resulting in an allowable U-shaped volume in the NO lumen(e.g., of 0.035 ml). In exemplary embodiments, changes in this minimumpulse volume and/or the optimal pulse volume range may impact at leastthe NO lumen size. For example, should the minimum pulse volume besmaller due to, for example, higher nitric oxide concentrations beingused, the inner diameter of the NO lumen and/or “U” volume may bedecreased to ensure the 10% error goal. For example, the NO lumen and/or“U” volume may be decreased taking into account the various metrics foroptimization such as, but not limited to, pulse shape. Further, forexample, should the minimum pulse volume be increased due to, forexample, the use of lower concentration nitric oxide, then the innerdiameter of the NO lumen and/or “U” volume may be increased. Forexample, the NO lumen and/or “U” volume may be increased taking intoaccount the various metrics for optimization such as, but not limitedto, pulse shape. It will be understood that if the NO lumen and/or “U”volume is too large (e.g., about 0.1 ml to about 0.5 ml) then smallvolume pulses may not be able to be delivered accurately, delivery maybe delayed, dilution may occur, and/or other problems may occur due tothe unique nature of NO delivery.

Minimizing Delay and/or Distortion

For nitric oxide delivery systems (e.g., that may pulse nitric oxide gasto patients) to have optimal clinical efficacy it may be necessary todeliver a pulse or flow of nitric oxide to the patient as early in theinspiratory phase as possible and/or with a desired flow waveform (e.g.,pulse shape). Noting this, pneumatic delays may be and/or should beminimized because, for example, pressure signals from the patient can beused as an indication of patient inspiratory effort and/or the beginningof patient inspiration. Also, distortion of pulse or flow waveforms maybe and/or should be minimized because, for example, waveform shapeand/or timing may be tied to clinical efficacy. Accordingly, one or moreembodiments of the present invention relate to nasal cannulaconfigurations that minimize the delay and/or distortion of pressuresignals, for example, when in transit through the cannula from thepatient back to the device and/or that minimize distortion of flowwaveforms.

In exemplary embodiments, the lumen of the cannula affiliated withtriggering (e.g., the triggering lumen; combined triggering and NOlumen; combined triggering, NO, and O2/air lumen; etc.) can beconfigured to minimize the delay and/or distortion of pressure signalswhen in transit through the cannula. To minimize the delay and/ordistortion of pressure signals when in transit through the cannula, thecross-section of the lumen affiliated with triggering can be selected toreduce delay and/or distortion and/or the cross-sectional size can beincreased and/or maximized to reduce delay and/or distortion.

In exemplary embodiments, the lumen of the cannula affiliated with NOdelivery (e.g., NO lumen; combined NO and triggering lumen; combined NO,triggering, and O2/air lumen; etc.) can be configured to minimizedistortion of flow waveforms. To minimize distortion of flow waveformsthe cross-section of the lumen affiliated with NO delivery can beincreased and/or maximized and/or the shape of the cross-section can beselected to reduce delay and/or distortion. Further, in exemplaryembodiments, to minimize distortion of flow waveforms the lumenaffiliated with NO delivery can be made having reduced compliance, i.e.,having increased stiffness. For example, to minimize distortion of flowwaveforms the lumen affiliated with NO delivery can be made of asubstantially rigid material. The rigidity of the material can beselected for reducing compliance while still factoring in at leastpatient comfort.

Completing Metrics

In at least some embodiments the cannula can be configured such that onelumen can be for delivering NO and be for triggering (e.g., mono-lumencannulas, dual-lumen cannulas, etc.). Such configurations can requireoptimizing the lumen for both NO delivery and for triggering to haveminimal dilution of NO doses as well as allow the trigger signal topropagate to the device without attenuation substantially over thespectral band of human breathing (e.g., 0-4 Hz). This can besubstantially difficult as these can be competing metrics foroptimization. For example, in order to deliver a pulse and/or flow of NOearly in the inspiratory phase, reduce pneumatic delays, reducedistortion of flow waveforms, reduce delay and/or distortion of pressuresignals, reduce the volume of NO mixing and/or NO oxidation at thenosepiece, and/or address any other desired property (e.g., for acombined NO/triggering lumen) several competing metrics of the lumen IDcan be optimized such as, but not limited to:

-   -   a. Reduce NO2 formation->Reduce lumen ID;    -   b. Maintain volumetric NO dosing accuracy->Reduce lumen ID;    -   c. Reduce NO flow distortion->Increase lumen ID; and    -   d. Minimize trigger signal attenuation or delay->Increase lumen        ID.

In exemplary embodiments, cannulas of the present invention that havecombined NO/triggering lumen configurations can require compromise ofthe optimal geometry (e.g., shape, size, etc.) of the NO/Trigger lumento, for example, deliver pulses and/or flows of NO early in theinspiratory phase, reduce pneumatic delays, reduce distortion of flowwaveforms, reduce delay and/or distortion of pressure signals, reducethe volume of NO mixing at the nosepiece, and/or NO oxidation at thenosepiece. Such compromise may be required for cannulas of the presentinvention that have combined NO/triggering lumen (e.g., mono-lumencannulas, dual-lumen cannulas, etc.). However, cannulas configurationsof the present invention that have at least three lumens (e.g.,tri-lumen cannula, quad-lumen cannula, etc.), as discussed below, canallow for lumens dedicated to both NO delivery and to the trigger signaland can, in at least some instances, allow for a dedicated O2/airdelivery lumen. As such, for cannulas of the present invention withdedicated lumens for NO delivery and triggering (e.g., tri lumencannulas, quad-lumen cannulas, etc.) the optimized NO lumen can besmaller than the optimized trigger lumen since it may be beneficial tohave a larger trigger lumen to ensure at least minimal signalattenuation while it may be beneficial to have a smaller NO lumen toreduce at least dilution of NO. As such, cannulas of the presentinvention having combined NO/triggering lumens (e.g., mono-lumen,dual-lumen cannulas, etc.) and cannulas of the present invention havingdedicated NO delivery lumens and dedicated triggering lumens (e.g.,tri-lumen cannulas, quad-lumen cannulas etc.) can have differentgeometries when optimized.

By way of example, in addition to ensuring the accuracy of volumetricdosing (e.g., described above with respect to minimizing dilutionresulting from retrograde flow), the ID of combined NO/triggering lumenscan be designed to reduce and/or not produce gas flow distortion and/orundue signal propagation delay, for example, from the patient to thedevice (e.g., described above with respect to minimizing delay and/ordistortion of pressure signals). Such distortion and/or delay may occuras pneumatic tubes may behave as first order pneumatic low pass filtersand attenuate higher frequency signal components. Modification of theinner diameters can change the band pass characteristics of thefiltering effect. However, as noted earlier, the inner diameter (e.g.,at the U) can be fixed to a certain maximum ID based on the requireddose delivery accuracy of the system.

In light of at least the above, in exemplary embodiments, to minimizethe effects of the potentially frequency attenuated pressure signal: (1)the upstream (close to device) diameter of the combined NO/triggeringlumen of cannulas of the present invention can be adjusted to widen(e.g., optimize) the band pass characteristics of the cannula and/or (2)triggering of the initiation of pulse delivery of NO (e.g., by thedelivery device) may have the typical threshold pressure triggerstrategy (e.g., the pressure signal may be attenuated and/or delayed bythe pneumatic filtering effect of the cannula construct) and thereforeit may be advantageous to supplement/replace this threshold pressuretrigger with a pressure slope based triggering strategy based on apattern of sloping pressure indicative of patient effort. Such apressure slope based triggering strategy in the presence of significantsignal attenuation can be more responsive (e.g., faster) to patienteffort. It will be understood that to minimize the effects of thepotentially attenuated/delayed pressure signal the downstream diameterof the combined NO/triggering lumen of cannulas of the present inventioncan be adjusted to widen (e.g., optimize) the band pass characteristicsof the cannula; however, this may produce an undesirable side effect ofthe cannula nosepiece size being increased, which in turn may make thecannula less comfortable to the patient.

In exemplary embodiments, the upstream diameter of the combinedNO/triggering lumen can be adjusted to widen the band passcharacteristics of the cannula to ensure that unneeded compressiblevolume may be unavailable upstream of the nose piece restriction (e.g.,0.046 inch ID restriction, etc.). This can reduce the compressiblevolume in the cannula and/or effectively increases the band passcharacteristics of the cannula.

In exemplary embodiments, triggering of dose delivery (e.g., by thedelivery device) can be based on a pattern of sloping pressureindicative of patient efforts and/or the slope can be reduced inmagnitude by the filtering characteristics of the tubing, however, theslope can still be present for algorithmic triggering decisions (e.g.,by the delivery device). In exemplary embodiments, triggeringmethodologies can be based not on pressure thresholds, rather triggeringmethodologies can be based on pressure slope trends that can also beemployed to improve overall timely delivery of dosing to the patient. Itwill be understood that such a triggering implementation can beoptional.

Mono-Lumen Cannula

Referring to FIG. 3A, in exemplary embodiments, the nasal cannula canhave at least one lumen (i.e. a mono-lumen cannula 300) that can delivernitric oxide in the same lumen as used to deliver oxygen and/or triggera delivery device 303. Using mono-lumen cannula 300, in a single lumen,oxygen and/or ambient air flow 305 can be delivered to a patient withdoses of NO 307 intermittently pulsed into the flow. This same lumen mayalso be used for triggering. Using this technique, retrograde flow canbe substantially reduced, for example, because the O2 and/or air caneffectively clear the cannula nosepiece after each NO pulse and orbecause the single lumen can be a closed system at the device upon valveclosure and thus flow into the cannula lumen can be prevented. However,using this technique, oxygen and/or air 305 can be in contact with NO307 within the lumen of cannula 300 and react (e.g., forming NO2)thereby diluting the intended NO dose.

In exemplary embodiments, a carrier gas can be used buffer (e.g.,insulate) the NO from O2 and/or a carrier gas can be used to increasethe effective volume of the delivered dose, for example, to reduce thetransit time of NO in the cannula. This buffer gas can be diffused intothe NO dose and/or surround the NO dose (e.g., spatially before andafter).

Referring to FIG. 3B, in exemplary embodiments, to reduce dilution of NO307 with oxygen and/or air 305 within the NO/O2 lumen, a buffer agent309 can be delivered between NO 307 and oxygen 305. By way of example,first oxygen can be delivered through the NO/O2 lumen, then a bufferagent (e.g., an inert gas, nitrogen gas, etc.) can be delivered, then NOcan be delivered, then another buffer agent can be delivered, and thenoxygen can be delivered. The buffer agent can reduce interaction betweenNO and oxygen thereby reducing dilution of NO, for example, caused byNO2 formation.

In exemplary embodiments, when using a buffer gas to transport the NOwithin the cannula the amount of contact between NO with O2 and the timeof contact can be minimized without substantially distorting the shapeof the NO pulse dose. In exemplary embodiments, the buffer gas can besubstantially devoid of O2 such that it can act as a buffer to anyentrained O2 and/or it can increase the volume of delivered gas therebydecreasing the time that the NO dose in the cannula. In exemplaryembodiments, the buffer gas can include oxygen, however, the diameter ofthe cannula lumen can be small enough so that the cross section of theNO dose exposed to O2 can be minimized and/or the diameter can be largeenough to ensure that the pulse shape of the dose may not besubstantially distorted.

In exemplary embodiments, a buffer gas can be provided by using the O2depleted gas mixture remaining after an oxygen concentrator system hasremoved the O2 from air.

It will be understood that the buffer disclosed can be used with anymulti-lumen cannula (e.g., dual-lumen cannula, tri-lumen cannula,quad-lumen cannula, etc.) where NO and O2 may be delivered in the samelumen. For example, a dual lumen cannula can have a trigger lumen andcombined NO/O2 lumen wherein NO may be intermittently pulsed into O2with a buffer separating the NO and O2.

In exemplary embodiments, the inner diameter of the mono-lumen (e.g.,combined NO/O2 lumen, combined NO/O2/Trigger lumen, etc.) can beconfigured to be substantially small, for example, to reduce residualgas mixing. As discussed above, lumens that include different functions(e.g., NO delivery, triggering, O2 delivery, etc.) can have competingmetrics for optimization. For optimization, the dimensions of thecross-section of the mono-lumen can require a compromise between atleast some of these competing metrics. For example, because themono-lumen has a combined NO/triggering lumen and/or combinedNO/O2/Trigger, the optimal geometry (e.g., shape, size, etc.) of themono-lumen can require compromise between at least some competingmetrics to, for example, deliver pulses and/or flows of NO early in theinspiratory phase, reduce pneumatic delays, reduce distortion of flowwaveforms, reduce delay and/or distortion of pressure signals, reducethe volume of NO mixing at the nosepiece, and/or NO oxidation at thenosepiece. Considering at least the competing metrics for optimization,in at least some embodiments, the inner diameter of the mono-lumen(e.g., combined NO/O2 lumen, combined NO/O2/Trigger lumen, etc.) can beless than about 0.07 inches.

Dual-Lumen Cannula

Referring to FIG. 4, in exemplary embodiments, the nasal cannula canhave at least two lumens (i.e. a dual-lumen cannula 400) that candeliver nitric oxide in a separate lumen (e.g., NO lumen 404) than theat least one lumen 406 that can deliver oxygen (e.g., from oxygen/airsupply 405) and/or that can trigger the delivery device (e.g., deliverydevice 403). The NO lumen can carry therapeutic gas comprising NO fromNO delivery device 403 to the patient (e.g., at cannula nosepiece 402).The two lumens can be aggregated into a single cannula nosepiece (e.g.,cannula nosepiece 402) that can have separate flow paths for each lumen.

In exemplary embodiments, the lumen (e.g., of the dual-lumen cannula)that carries the nitric-oxide containing gas can have a substantiallysmall inner diameter that may be smaller than the other lumen(s) (e.g.,the triggering lumen, oxygen lumen, etc.). In at least theseembodiments, having a substantially small inner diameter for the lumenthat carries NO the cannula can reduce dilution by at least thefollowing mechanisms: (i) minimizing mixing of oxygen and NO because ofa reduction in retrograde flow into the small ID NO carrying lumen dueto the smaller ID; (ii) minimizing the bulk volume of gas mixing becausethe volume of NO gas per unit length can be reduced by having a small IDNO caring lumen; and/or (iii) the small ID NO carrying lumen can producea narrow jet of gas flow which can effectively minimize O2/NO mixingduring NO delivery and/or can minimize O2/NO mixing during NO deliveryuntil much further into the nasal cavity. Similar mechanisms forreducing dilution can be accomplished by reducing the ID of the lumenfor NO delivery used in other multi-lumen cannulas described herein(e.g., tri-lumen cannulas, quad-lumen cannulas, etc.).

In exemplary embodiments, the diameter of the small lumen can beminimized such that it can be as small as reasonably possible withoutproducing confounding upstream effects on the flow delivery mechanics ofthe device. For example, in one or more embodiments, the NO lumen mayhave an ID in the range from about 0.01 inches to about 0.10 inchesand/or about 0.03 inches to about 0.08 inches. Further, in one or moreembodiments, the oxygen lumen and/or trigger lumen (e.g., dedicatedtrigger lumen, etc.) may have an ID in the range from about 0.05 inchesto about 0.20 inches and/or about 0.08 inches.

Referring to FIGS. 5A-5B, in exemplary embodiments, a dual-lumen cannulacan have a first lumen 502 for oxygen delivery and a second lumen 504for delivery of NO and transmitting the pressure signal for the triggersensor of delivery device 505. In this configuration, first lumen 502can carry oxygen from an oxygen conserver/concentrator 507 to thenosepiece 506 of the cannula. Second lumen 504 can deliver NO from thenitric oxide delivery device to the patient and/or can deliver thepressure-based triggering signal from the patient to trigger sensor ofthe nitric oxide delivery device. Both lumens can be constructed toconnect (e.g., tee) to both nares 508/510 and thus be in unobstructedfluid communication with both nares 508/510.

The first lumen for carrying oxygen can be constructed with a lumeninner diameter geometry consistent with industry norms. For example, anasal cannulas with rated 6 LPM oxygen delivery capacity can have anoxygen lumen inner diameter of approximately 0.08 inches at, or near,the nosepiece. Accordingly, in one or more embodiments, the oxygen lumencan have an inner diameter in the range of about 0.05 inches to about0.20 inches and/or about 0.08 inches.

The second lumen for carrying NO and triggering can be constructed basedon compromise of competing metrics (e.g., as discussed above). Forexample, because the second lumen combines carrying NO and triggering,the optimal geometry (e.g., shape, size, etc.) of the second lumen canrequire compromise between at least some competing metrics to, forexample, deliver pulses and/or flows of NO early in the inspiratoryphase, reduce pneumatic delays, reduce distortion of flow waveforms,reduce delay and/or distortion of pressure signals, reduce the volume ofNO mixing at the nosepiece, and/or NO oxidation at the nosepiece.Considering at least the competing metrics for optimization, in at leastsome embodiments, the geometry of the combined NO/Trigger lumen of thedual-lumen cannula can be in the range of about 0.08 inches. Inexemplary embodiments, the internal diameter of the second lumen can bedictated by volumetric dosing accuracy considerations, the second lumencan have an ID in the range of about 0.01 inches to about 0.10 inches,and/or the second lumen can have an ID in the range of about 0.01 inchesto about 0.06 inches with upstream tubing that can be adjusted tooptimize (e.g., widened, etc.) the band pass performance of the system.

In exemplary embodiments, a dual-lumen cannula can have a first lumenfor NO delivery and a second lumen for delivery of O2 and transmittingthe pressure signal for the trigger sensor of delivery device. In thisconfiguration the NO lumen can be substantially small (e.g., havingsimilar dimensions to the NO lumen described below in a tri-lumencannula) and/or the combined O2 and triggering lumen can have an innerdiameter in the range of about 0.07 inches to about 0.14 inches and/orabout 0.03 inches to about 0.08 inches at the nosepiece. In exemplaryembodiments, a dual-lumen cannula can have a first lumen for NO and O2delivery and a second lumen for transmitting the pressure signal for thetrigger sensor of delivery device. In this configuration, the firstlumen for NO and O2 delivery can utilize similar techniques fordelivering NO and O2 in the same lumen, for example, as described hereinwith reference to a mono-lumen cannula.

Tri-Lumen Cannula

Referring to FIGS. 6A-7, in exemplary embodiments, the nasal cannula canhave at least three lumens (i.e. a tri-lumen cannula 600): one lumenthat can deliver nitric oxide in a lumen (e.g., NO lumen 604), forexample, from a delivery device (e.g., delivery device 603); anotherlumen that can be for triggering (e.g., triggering lumen 606), forexample, the delivery device (e.g., delivery device 603); and anotherlumen that can deliver O2 in a lumen (e.g., O2 lumen 608), for example,from an O2/air source (e.g., conserver and/or concentrator 605). Thethree lumens can be aggregated into a single cannula nosepiece (e.g.,cannula nosepiece 602) that can have separate flow paths for each lumenand/or at least one lumen.

The NO lumen can be a dedicated lumen that can carry therapeutic gascomprising NO from NO delivery device 603 to the patient (e.g., vianares 610/612 at cannula nosepiece 602). The oxygen lumen can be adedicated lumen that can carry an oxygen-enriched gas (e.g., such asoxygen-enriched air, substantially pure oxygen, etc.) from an oxygensource to the patient (e.g., via nares 610/612 at cannula nosepiece602). The oxygen source can be an oxygen pulsing device (e.g., such asan oxygen conserver) and/or a constant flow oxygen device (e.g., such asan oxygen concentrator) and/or can be a port on the NO delivery devicethat delivers the oxygen-enriched gas. The trigger lumen can be adedicated lumen that allows propagation of triggering signals from thepatient to NO delivery device 603.

In exemplary embodiments, the nasal cannula can connect the oxygen lumento an oxygen source (e.g., an oxygen pulsing device, an oxygenconserver, a constant flow oxygen device, oxygen concentrator, etc.)and/or the nasal cannula may not connect the oxygen lumen to an oxygensource (e.g., for patients who are not receiving supplemental oxygen).For patients who are not receiving supplemental oxygen, the oxygen lumenmay be removed and/or may be partially removed. For example, the oxygenlumen may be partially preserved to support the oxygen side of thecannula which goes around the patient's head while the lumen portionproviding the connection to an oxygen source (e.g., an oxygen pigtailoff of the reducer) may be removed. Removal and/or partial removal ofthe oxygen lumen can similarly be done for other multi-lumen cannulasdescribed herein (e.g., dual-lumen cannulas, quad-lumen cannulas, etc.).

Referring to FIGS. 6C and 7, an exemplary cannula can include threelumens at the nosepiece (e.g., nose bridge fitting, etc.) and/or thepneumatic paths and/or lumina can be separated by partitions and/ordiaphragms that may be within the nosepiece and/or nares of the cannula.The NO supply can traverse the nosepiece through a lower gas resistancesource to higher resistance orifices that can be included into the naresof the cannula. In exemplary embodiments, each lumen may be separated bya diaphragm partition within the nosepiece of the cannula and/or withinthe nares of the cannula to prevent mixing of the fluid streams in theseparate lumens.

The three lumens can be extruded through a single die producing amulti-lumen tube, can be extruded in a single multicavity extrusion, canbe extruded separately and affixed together in a paratube arrangementdisclosed herein, and/or using any other reasonable technique. Similartechniques can be used for other multi-lumen cannulas described herein(e.g., dual-lumen cannulas, quad-lumen cannulas, etc.).

Referring to FIG. 7, in exemplary embodiments, the NO deliverylumen/tube 604 can decrease in inner diameter (ID) at least once whenjust about to, and/or just after, entering the nasal cannula nosepiece602. Accordingly, in one or more embodiments, the pneumatic resistancemay be greater in the nares of the nasal cannula than in the tubingcarrying the NO from the NO delivery device to the cannula nosepiece. Inexemplary embodiments, the smaller ID tubing of the dedicated NOdelivery lumen can allow for advantages such as, but not limited to:

-   -   Short gas transit times;    -   Reduced inspiratory/expiratory phase retrograde flow of ambient        air into the lumen (e.g., reduced according to Knudsen diffusion        which states that diffusion rate is proportionate to the mean        free path length of the gas molecule which can be reduced with        smaller ID);    -   Increased gas resistance to flow (e.g., smaller ID tubing        produces gas flow resistance which can be inversely proportional        to the fourth power of tubing radius by Poiseuille's Law); and    -   Reduced volume in the tee'd loop of the NO delivery lumen.

The above can reduce the potential for retrograde flow, reduce thevolume of retrograde flow, and/or reduce the contact and/or contactduration between NO and other gasses including oxygen in the cannula, toname a few. This in turn can reduce the dilution of NO and/or therebyincrease the precision of the delivered NO dose. Accordingly, inexemplary embodiments, the ID of the NO lumen can be about 0.01 inchesto about 0.10 inches and/or about 0.07 inches.

The ID of the NO lumen can decrease from a maximum ID to a minimum ID,for example, to at least reduce cross flow and/or increase patientcomfort. In exemplary embodiments, the ratio of the minimum ID to themaximum ID of the NO lumen can be, but is not limited to, 1:1, 1:1.2,1:1.3, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:7,1:8, 1:9, and/or 1:10, to name a few. Similar ratios of the minimum IDto the maximum ID of the NO lumen can be used for other multi-lumencannulas (e.g., dual-lumen, tri-lumen, quad-lumen cannula, etc.)described herein that can have dedicated lumens for NO delivery and/orcombined NO delivery and triggering lumens.

The trigger lumen ID can be comparatively much larger than the NO lumenID. The trigger lumen ID can be substantially larger so that triggerpressure drop on inhalation can be transmitted through this cannulalumen with the smallest possible loss of signal magnitude and/or phasedelay to the NO delivery device which in turn can use this pressuresignal to deliver pulsed NO. Accordingly, in exemplary embodiments, theID of the trigger lumen can be about 0.05 inches to about 0.20 inchesand/or about 0.08 inches. In exemplary embodiments, the ratio of the IDof the NO lumen to the ID of trigger lumen can be, but is not limitedto, 1:1, 1:1.2, 1:1.3, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5,1:5.5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:15, 1:20, 1:25, and/or 1:30, toname a few.

The oxygen lumen can also be larger than the NO lumen, for example, tominimize oxygen flow resistance and/or to reduce gas flow speed at thenares which can serve to interfere with the triggering pressure signaldue to gas flow effects (e.g., such as from Bernoulli's principle)and/or to reduce high frequency (e.g., auditory range) resonance withhigh speed oxygen transit to reduce the “noise” associated with oxygendelivery. Accordingly, in exemplary embodiments, the ID of the oxygenlumen can be about 0.05 inches to about 0.20 inches and/or about 0.08inches. In exemplary embodiments, the ratio of the ID of the NO lumen tothe ID of the oxygen lumen can be, but is not limited to, 1:1, 1:1.2,1:1.3, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:7,1:8, 1:9, 1:10, 1:12, 1:15, 1:20, 1:25, and/or 1:30, to name a few.

Quad-Lumen Cannula

Referring to FIGS. 8A-8D, in exemplary embodiments, the nasal cannulacan have at least four lumens (i.e. a quad-lumen cannula 800): twolumens that can deliver nitric oxide in a lumen (e.g., NO lumen 804A and804B), for example, from a delivery device (e.g., delivery device 803);another lumen that can be for triggering (e.g., triggering lumen 806),for example, the delivery device (e.g., delivery device 803); andanother lumen that can deliver O2 in a lumen (e.g., O2 lumen 808), forexample, from an O2/air source (e.g., conserver and/or concentrator805). The four lumens can be aggregated into a single cannula nosepiece(e.g., cannula nosepiece 802) that can have separate flow paths for eachlumen and/or at least one lumen.

In exemplary embodiments, like the pneumatic configurations discussedabove, this configuration can separate the pneumatic paths of the NO,oxygen, and trigger. Further, in exemplary embodiments, the NO flowdelivery paths to each nostril can be kept separate and distinct and/orhave their own pneumatic delivery source at the NO delivery device.

Referring to FIG. 8D, an exemplary quad-lumen cannula having the aboveconfiguration can be constructed at the cannula nosepiece wherein thequad-lumen cannula can fuse the lumen of the cannula into a singleumbilical between the cannula nosepiece and the device, for example, asmay be similarly done with the tri-lumen cannula. Similar to thetri-lumen cannula (e.g., as described referring to at least FIG. 7), NOdelivery lumen/tube 804A and 804B can decrease in inner diameter (ID) atleast once when just about to, and/or just after, the tubing enters thenasal cannula nosepiece 802. Accordingly, in one or more embodiments,the pneumatic resistance may be greater in the nares of the nasalcannula than in the tubing carrying the NO from the NO delivery deviceto the cannula nosepiece.

In exemplary embodiments, the dimensions of the triggering lumen 806,oxygen lumen 808, NO lumens 804A and 804B can be similar to therespective lumens in the tri-lumen cannula and/or the geometry of theselumens can provide similar benefits as those described above withrespect to the tri-lumen cannula.

Further to the above benefits, the quad-lumen cannula configuration can,amongst other things, prevent movement of gas through the connected(e.g., tee'd) delivery loop of the NO supply line during exhalation.This can reduce NO/oxygen contact and/or reduce or substantiallyeliminate cross flow. In at least some instances, use of the quad-lumencannula can require dedicated pneumatic circuitry for each NO lumen.

In exemplary embodiments, the quad lumen cannula configuration caninclude two triggering lumens (e.g., one two each nostril) as well as anNO delivery lumen and an O2 delivery lumen. Of course otherconfigurations are within the scope of the invention.

Check Valves and Valves

In one or more embodiments, a nasal cannula (e.g., single lumen cannula,multi-lumen cannula, any of the nasal cannulas disclosed herein, etc.)can include one or more check valves that can be located in, and/or influid communication with, the nitric oxide delivery line. Further, inexemplary embodiments, one or more check valves located in, and/or influid communication with, the nitric oxide delivery line can be combinedwith any of the multi-lumen configurations described. Check valves canbe used to, amongst other things, prevent retrograde gas movement intothe NO supply lumen during inhalation/exhalation. Check valves can beany low cracking pressure check valve which can be placed at some pointin, and/or in fluid communication with, the NO delivery path. Such checkvalves can include, but are not limited to, duckbill valves, umbrellavalves, and/or any other valve.

Referring to FIG. 9A, exemplary duck bill valve 902 and/or referring toFIGS. 9B-9C exemplary umbrella valves 904 are illustratively depictedthat can be used in accordance with nasal cannulas of the presentinvention. These check valves can be miniature check valves, forexample, so they can have the dimensions to fit in the NO delivery lumenand/or be in fluid communication with the NO delivery lumen and/or theymay be constructed out of the lumen itself by appropriately shapingand/or slitting the lumen outlet during the molding and/or manufacturingprocess.

Referring to FIG. 10, in one or more embodiments, the NO deliverycannula and/or lumen can have a small flapper and/or umbrella checkvalve 1000 that can be located at the cannula nosepiece 1002 and/or thatcan allow pulses of NO to be delivered to the general nose/mouth areaduring device NO pulsing. This configuration can allow NO to flow intoeither and/or both open nares upon inhalation and/or can restrictretrograde flow into the NO lumen (e.g., during exhalation). The O2and/or trigger lumen can be combined or kept separate from the NO lumen,for example, to reduce any adverse signal-to-noise ratio impact on theperformance of the trigger lumen due to oxygen flow. Such aconfiguration with the flapper valve can prevent retrograde flow ofoxygen into the NO delivery path thereby reducing the potential fordilution of the dose. A diaphragm and/or other barrier can separate theNO delivery line from the O2/trigger line at the cannula nosepiece, forexample, to prevent mixing.

In one or more embodiments, the nasal cannula can incorporate animpermeable and/or semi-permeable membrane that can be movable or fixedand/or can be actively or passively moved when needed. Further, themembrane can separate the NO containing gas or material from the O2containing gas or material, for example, until the NO needs to bedelivered to the patient. This membrane can reduce the contact time,surface area, and/or diffusion rate between the NO and O2 containinggases. This can reduce the formation of NO2, which can dilute theintended NO delivery concentration.

Referring to FIG. 11A, in one or more embodiments of the invention, anormally-closed valve 1100 (e.g., a duck bill valve, flap valve,pressure valve, etc.) at the substantially at, and/or near, the end ofthe NO containing cannula, NO lumen, and/or nosepiece of the cannula canprevent air from contacting the NO containing gas inside the cannula,for example, until the valve opening may be triggered (e.g. by a drop inpressure caused by inhalation by the patient or by the positive pressurecaused by the delivery device as it attempts to deliver the NOcontaining gas to the patient). When the valve opening is triggered, theNO can then be delivered to the patient.

In one or more embodiments, a system can be used and/or provided toexpel the gas or other NO containing material that come in contact withO2 containing gas or material, which can have otherwise formed NO2 inthis mixture. The system can subsequently allow another part of the NOcontaining gas or material that has minimal or no NO2 to be delivered tothe patient.

Referring to FIG. 11B, in one or more embodiments of the invention, thesystem and/or nasal cannulas can include and/or be in fluidcommunication with an electromechanical valve system 1104 that canactuate, for example, to pump out a fixed or adjustable amount of gasmixture that might contain NO2 through a separate orifice than thecannula opening to the patient. The system can then actuate to pump theNO containing gas or material to the patient.

It will be understood that the any of above teachings (e.g., checkvalves, check valve configurations, membranes, valves, electromechanicalvalve systems, etc.) can be combined with any of the other pneumaticconfigurations, cannula configurations, and/or teachings and/orembodiments described herein. For example, the above teachings (e.g.,check valve configurations, etc.) can be used with the mono-lumencannulas or multi-lumen cannulas described herein and/or any otherteachings and/or embodiments described herein.

Minimizing NO/O2 Contact During Connection to Source

One or more embodiments of the present invention relate to nasalcannulas and/or systems that reduce NO/O2 contact during the connectionof the high pressure source (e.g., a pressurized cylinder, etc.) to thedelivery device (e.g., one or more of the above sources of oxygen/NOcontact) and thereby dilution of the intended NO dose using a three wayvalve. For example, nasal cannulas and/or systems of the presentinvention can include a three way valve with one port to ambient thatcan be configured so that the three way valve opens to ambient uponconnection of the canister to remove (e.g., blow off) the oxygen.

Proportional Nostril Delivery

Referring to FIGS. 12-13, one or more embodiments of the presentinvention relate to nasal cannulas and/or systems that address theproblem of drug loss (e.g., to the ambient environment) when deliveringa gaseous drug (e.g., in the form of pulsed nitric oxide, etc.) througha nasal cannula due to at least a partially occluded nasal passage(e.g., as shown in FIG. 12). By way of example of such a problem, if oneside of the nose (e.g., nose 1201) is occluded (e.g., occlusion 1203)and the drug is being delivered to both sides of the nose through acannula/delivery system 1200 which does not discriminate how much of thedrug goes to either nostril (e.g., nostrils 1205), then there can bedrug loss due to the occluded nostril. In addition, there may be otherundesired consequences such as the reaction of the unused therapy gaswith other materials and/or compounds that may come in contact with thegas.

This inadequate dosing can be a particular problem when delivering thedrug therapy in set limited quantities, such as when pulsed (e.g., whendelivered synchronous to a patient's breathing pattern and rhythm)through a single lumen exiting the delivery device that in turn may thenbe split at some point downstream before reaching the patient. Further,this can be a particular problem because, when pulsing the drug dosethrough a single lumen that is then split, the dose can be equally orsubstantially equally split in the two streams without consideration forthe blockage in the nose downstream of the split. Thus a significantpart (e.g., up to half) of the dose may not be delivered to the patientand/or may remain in the vicinity of the blocked or obstructed nares.

One or more embodiments of the present invention relate to nasalcannulas and/or systems that solves or minimize the above problem by,for example, providing for the roughly proportional delivery of thetherapy to each nares with the delivery being proportional to the flowof air and gas in the nares and/or inversely proportional to theresistance in the nares. This can be achieved by using the driving forceof the patient's breathing, which can be generally and roughlyproportional to the flow rate of air/gas into each of the nares, toproportionally split and/or pull the therapy gas into the patient's noseand subsequently into the patient's lungs. This system can deliver thedose to a patient in such a way as to ensure that the designed, set, oradequate dose can be delivered proportional to the flow of air in eachnostril (or inversely proportional to the resistance of each nostril)such that the partial or full blockage (whether permanent or transient)of either or both nostril doesn't affect the amount of drug delivered tothe patient.

For example, the cannula/lumen can be designed to deliver a desiredquantity of the therapeutic gas such that the delivered dose can beinjected and/or delivered into a flowing stream of inspiratory air,driven by the patient's breathing, with such flow splitting, downstreamof the point of delivery of the drug, proportional to the amount of airgoing into each nostril or simply delivered to one nostril if the othernostril's flow is below a predetermined threshold such that thedelivered drug can also be split proportional and/or roughlyproportional or directed to one or the other nostril in an all or noneconfiguration based on the higher flowing nostril to the said flow ofgas. The flow of air in a stream to the patient can be achieved byhaving a flow path from the ambient air (e.g. through a simple hole inthe nose piece of the cannula) to each nostril such that this flow pathcrosses the delivery point/area/volume of the drug before moving on tothe split point leading to each nostril.

In exemplary embodiments, exemplary cannula/lumen configurations canallow the NO delivery to each nostril by injecting NO into a flow ofambient air going to each nostril (e.g., as shown in FIG. 13) and/orconfigurations can allow a beneficial cross flow between the two naresthat can be designed and/or used to help guide NO to the uncloggednostril (e.g., as shown in FIG. 12). The delivery cannula/lumen can bedesigned to ensure the therapeutic gas cannot be entrained or streamedout of the path of flow of air into the patient. The deliverycannula/lumen and the flow path of inspiratory air to the patient can bedesigned to ensure that the delivery of the drug into the stream of aircannot be hampered or accelerated by creation of backpressure or partiallower pressure or other disruptive flow patterns at the point ofinjection of the drug into the ambient stream of air. The deliverycannula/lumen, the flow path of inspiratory air, the split of the airflow into the nostrils, and the individual lumen pieces in the nares canbe designed to ensure that there can be adequate flow of air versusother sources of air or oxygen to the patient such that the drug can beentrained and carried into the nares proportional or substantiallyproportional to the flow of air in the nostrils.

Independent Nostril Delivery

One or more embodiments of the present invention relate to nasalcannulas and/or systems that address the problem of inadequate dosingdue to a partially or completely blocked nostril by, for example,detecting and/or determining the amount of driving force in each nostriland adjusting the amount of drug delivered to each of the nares. Thiscan be accomplished by using valves, baffles, flaps, and/or any otherdevice to ensure proportional and/or substantially proportional dosingin each nostril.

Addressing at least the above, dual channel systems (e.g., that may workwith multi-lumen cannulas such as quad-lumen cannulas) can utilize atleast two independent flow channels: one to each nostril. In exemplaryembodiments, these independent flow channels can have drug flowstailored to the inspiratory draw of each nostril, for example, byconfiguring the flow channels to deliver flow proportional to the drawof each nostril with total flow to both nostrils summing to theappropriate dose and/or by configuring the flow channels to deliver tothe single working (e.g., high flow draw nostril) if the flow draw ofthe occluded nostril falls below a preset threshold.

Referring to FIGS. 14A-14B, in order to implement such a dual channelsystem, it may be necessary to have two independent flow deliverychannels coupled by a single (global) controller module (e.g., a controlmodule associated with a delivery device, etc.). Each of these deliverychannels can require a pressure and/or flow signal from the particularnostril of interest as well as the ability to deliver the gas to thenostril. By way of example, as illustrated in FIG. 14A, cannula 1400 canhave separate sensing lumens 1402 and delivering lumens 1404 for eachnostril (e.g., a dual lumen cannula, tri-lumen cannula, quad-lumencannula, etc.). By way of another example, as illustrated in FIG. 14B,cannula 1410 can have combined sensing and delivering lumens 1412 foreach nostril in which the triggering or breath detection signal can bedetermined and/or detected and drug delivered through the same lumen ofthe cannula (e.g., a single lumen cannula, dual-lumen cannula, etc.) asillustrated in FIG. 14B.

Referring to FIG. 15, in exemplary embodiments, pneumatics systems 1500(e.g., the delivery device) for the cannula may need to be implementedin order to support the above configurations of lumens (e.g., asdescribed above) and/or may require configurations having (1) a pressuresensor(s) 1502 and/or integral flow sensor(s) 1504 which can monitoreach channel independently or in pneumatic isolation and/or (2) a flowdelivery mechanism(s) which might have software controlled (on-off type)solenoid valve(s) and/or software controlled proportional solenoidvalve(s) 1506. Configurations using a pressure and/or flow sensor(s) caninclude a dedicated pressure and/or flow sensor for each deliverychannel and/or a valve switched pressure and/or flow sensor(s) which canalternate between delivery channels and/or determine and/or detectpressure and/or flow readings for each channel in isolation. Pressureand/or flow can be measured (e.g., using pressure sensor(s) 1502,integral flow sensor(s) 1504, etc.) independently and/or differentiallyusing one or more sensors. Further, one or more valves can actuate(e.g., independent, in tandem, proportionally, etc.) to deliver theappropriate amount of therapeutic gas.

In exemplary embodiments, the pneumatics channels can be controlled by acontroller and/or an embedded (global) controller module that can becapable of independent control of both channels, for example, to ensureproper overall dosing. This controller can receive input from thepressure or flow sensor(s) (e.g., two separate pressure sensors, asingle pressure sensor that can obtain the two pressure measurements inisolation, etc.) and can control both solenoid valves to achieve theproper dosing regimen.

Manufacturing of Multi-Lumen Nasal Cannulas

As described above, the individual lumen of a multi-lumen cannula can beseparately manufactured and then affixed to each other (e.g., paratubearrangement, etc.) and/or the multiple lumina can be extruded through asingle die producing a multi-lumen tube.

According to one or more embodiments, the multi-lumen nosepiece of themulti-lumen cannulas described herein can be manufactured using moldingtechniques. For example, the cannula can be manufactured to have atriple lumen cannula nosepiece for separate oxygen, nitric oxide, andtriggering lumina.

Referring to FIG. 16, in one or more embodiments, nosepiece 1602 for atri-lumen cannula can include three lumens, two lumens with innerdiameters of about 0.08 inches (e.g., for oxygen lumen 1608 and/ortriggering lumen 1066) and one lumen with a smaller inner diameter ofabout 0.045 inches (e.g., for nitric oxide lumen 1604). Thisconfiguration may not be readily molded by typical injection moldingtechniques, for example, as the small lumen may require an injector pin(of outer diameter about 0.045 inches) which may be too small to berobust (e.g., able to withstand substantially large numbers of shotpieces without bending) in a molding tool designed to last for manyuses.

Referring to FIG. 17, to manufacture the multi-lumen cannula nosepiece amold(s) can be used that can have at least two halves (e.g., 1701 and1702) in urethane, PVC, silicone, and/or other low durometer elastomerwith the internals of the large lumen 1704 and 1705) (e.g., oxygenlumen, trigger lumen, etc.) being defined by larger injector/core pins(outer diameter of about 0.08 inches) and with small half lumen indents(e.g., 1706 and 1708) defining the outline of the small lumen (e.g., NOlumen). These two halves can then be folded and bonded together,preferably with a bonding technique which does not produce residue orflash such as RF welding and/or solvent bonding, to form a wholenosepiece.

In exemplary embodiments, to circumvent the injector pin limitation withthe small ID lumen being defined by indents in the halves, the twohalves can be molded flat in one shot, for example, with a webbing(e.g., webbing 1709) holding the halves together and providing grossalignment during the folding and bonding process. The molded halves can,in some instances, include integral holes and mating cylindrical tabs orother complementary members (e.g., tab 1710 and tab mate 1712) so thatthe halves can be properly aligned when folded together. The webbing canalso be optional, for example, if appropriate complementary indexingmembers on the two halves ensure that the two portions forming the outerwall of the NO lumen can be properly aligned. The assembled nosepiececan allow for three lumen inputs and can be connected (e.g., tee'd) toeach lumen input within the internals of the nosepiece proper. Of coursethe nosepiece can be constructed using any reasonable technique. By wayof example, a nosepiece with a substantially small NO lumen can also beconstructed using liquid silicon rubber injection molding (e.g., a lowpressure molding technique in which a more robust mold tool may beachieved), and/or using a low pressure molding technique. Further, anosepiece with a substantially small NO lumen can be constructed usingmicromolding techniques known in the art which may be used for highresolution production of small parts including parts with small moldpins. By way of example a nosepiece with a substantially small NO lumencan be constructed using micro-molding techniques known in the art.

Referring to FIG. 18 a perspective view of the nare (e.g., nare 1716) ofthe multi-lumen cannula nosepiece of FIG. 17 is illustratively depictedafter the two halves have been assembled.

The lumen ID can be adjusted as described above. For example, the ID ofthe oxygen lumen can range from about 0.05 inches to about 0.20 inches,the ID of the trigger lumen can range from about 0.05 inches to about0.20 inches, and the ID of the NO lumen can range from about 0.01 inchesto about 0.10 inches. In one or more embodiments, the IDs of the oxygenlumen and the trigger lumen can both be in the range from about 0.07inches to about 0.09 inches and/or about 0.08 inches and the ID of theNO lumen can be in the range from about 0.035 inches to about 0.055inches and/or about 0.045 inches.

Referring to FIG. 19A-19B, within and/or before nare 1900 the small NOlumen 1902 can exit proximal to and/or within the larger trigger lumen1904, for example, so that any tip blockage of the larger trigger lumen(for which there may not be a purge capability) can be blownout/expelled by the function of the NO pulse. The geometry can bedesigned to ensure that all, and/or substantially all, NO in the largertrigger lumen can reach the respiratory system during inspiration and/ornot be left behind so that it may be swept out during exhalation.

Exemplary Nasal Cannula

Referring to FIG. 20, in accordance with exemplary embodiments, a nasalcannula 2001 is shown that includes three separate lumina for thedelivery of oxygen, delivering NO, and for breath triggering. The nasalcannula can include a nosepiece 2002 for interfacing with the patient'snose. NO lumen 2003 and triggering lumen 200 can carry NO to the patientand transmit the pressure signal, respectively. NO lumen 2003 andtrigger lumen 2004 can both be tubes (e.g., D-shaped tubes), such thattheir combined tubes appear as a single tube “paratube” 2003/2004.Paratube 2003/2004 can connect to the NO delivery device by nasalcannula connection piece 2014. Nasal cannula 2001 can further includekeying member 2010, reducer 2012, and/or oxygen connection piece 2016discussed in greater detail below.

Referring to FIG. 21A, the “paratube” can be formed by two tubes (e.g.,two D-shaped tubes). By way of example, the D-shaped tubes can beextruded separately and/or joined in a later operation, for example, byadhering (e.g., adhesive, glue, etc.) and/or bonding (e.g., heating,melting, etc.) to form a single paratube which can appear to be a singletube. Further, the flat interface between the tube halves can be alteredto have a tongue and groove type configuration enabling easy alignmentof the tubes relative to each other for a subsequent bonding operation.By way of another example, the D-shaped tubes can be extruded in oneoperation and later split at the ends (e.g., using a splicer). Further,the D-shaped tube extrusions can be of the same materials and/or ofdifferent materials. For example, the D-shaped NO tube can beconstructed of oxygen resistant materials and/or the other D-shape tubecan be constructed of PVC and/or other commonly used materials for tubeconstruction. Paratube 2003/2004 can connect to the NO delivery deviceby nasal cannula connection piece 2014.

Referring to FIGS. 21B and 21C, in exemplary embodiments, the innerdiameter of the tubes (e.g., NO lumen 2003, trigger lumen 2004, oxygenlumen 2008, combined lumens, etc.) and/or paratube can include geometricprotrusions (e.g., nubs, ribs, etc.) and/or inserts (e.g., tabs, etc.)to prevent complete tube occlusion, for example, due to kinking of thetube and/or tube compression. This geometric protrusions can be radiallyspaced such that they can be symmetrically and/or asymmetrically locatedwithin the tube and/or paratube.

Referring to FIGS. 20 and 22A-22E, nasal cannula connection piece 2014can be constructed to ensure fluid communication between the patient andthe device. The connection piece can be plugged into the device and/orcan be designed such that unidirectional connection may be required(e.g., such that it cannot be installed backwards). Further theconnection piece can include additional features such as, but notlimited to, a color stamped and/or differentially reflective area thatcan be used with IR sensing/detection to confirm insertion and/or theconnection piece can include a strain relief component 2202 (e.g., asshown in FIGS. 22C-22E), that may be integral to the connection piece,to prevent kinking of the tubing, for example, as the tubing exits theconnector. Of course, other techniques can be used to ensureintersection sensing/detection. Nasal cannula connection piece 2014 caninclude ribbing and/or substantially soft exteriors to aide in at leasthandling and removal of elements; strain reliefs, for example, that canbe for preventing kinking. Nasal cannula connection piece 2014 can beconstructed to ensure that seating of the connector in its socket can besensed or seen by the user; to name a few.

Referring to FIGS. 20 and 23, in exemplary embodiments, oxygenconnection piece 2016 an allow for connection to external oxygen supplydevices such as, but not limited to, oxygen conservers and/orconcentrators. Oxygen connection piece 2016 can be designed withindustry standard dimensions, for example, to ensure ease of use and/orconnection with oxygen supply devices. Further, oxygen lumen 2008 canconnect to an oxygen conserver or other oxygen delivery device by oxygenconnection piece 2016.

Referring to FIGS. 20 and 24, the NO lumen 2003, trigger lumen 2004, andoxygen lumen 2008 each can have a smaller inner and/or outer diameter bythe cannula nosepiece 2002 than at the relative connection pieces 2014and 2016. Accordingly, a reducer 2012 may be used to connect portions ofthe nasal cannula lumina that have different dimensions and/or crosssectional profiles. Further, reducer 2012 may also be used to terminatethe oxygen lumen, for example, when no oxygen pigtail is provided, whenreceiving ambient air into the cannula and/or when the nasal cannula isnot attached to an oxygen source, to name a few.

In exemplary embodiments, tubes (e.g., NO lumen 2003, trigger lumen2004, oxygen lumen 2008, combined lumens, etc.) can be attached tocannula nosepiece 2002 and/or device connector (e.g., connection pieces2014 and 2016) using any technique such as, but not limited to, bonding,adhesives (e.g., epoxy, cyanoacrylate, etc.), solvent bonding, insertmolding, and/or by any other technique.

Referring to FIG. 24, reducer 2012 can allow for a transition between,and/or connection between, tubes of different dimensions (e.g.,different outer diameters, different inner diameters, etc.) so tubing,for example, closest to the patient, can be optimized for patientcomfort (e.g., increasing flexibility, reducing outer diameterdimensions, etc.) and/or so that the pneumatic performance of each lumenof the cannula can be optimized using multiple diameters, for example,to optimize patient comfort by minimizing the tubing diameters locatedproximal to the patients head.

Nosepiece

Referring to FIGS. 25A-25Q various views of various exemplary cannulanosepieces 2002 are illustratively depicted. FIG. 25A shows the side ofcannula nosepiece 2002 in which the oxygen lumen 2008 connects tocannula nosepiece 2002. FIG. 25B shows the two D-shaped openings for theNO lumen 2003 and the trigger lumen 2004. FIG. 25C shows each prong ofthe nasal cannula connection piece having a central lumen for NO and twoexterior lumina for oxygen and triggering.

In exemplary embodiments, the cannula nosepiece and/or at least some ofthe cannula nosepiece and/or cannula can have a material properties(e.g., durometer, etc.) selected to provide the comfort while ensuringthe structural and pneumatic integrity (e.g., of the cannula nosepiece,at least some of the cannula nosepiece, at least some of the cannula,etc.). For example, to provide comfort while ensuring structural andpneumatic integrity, the cannula nosepiece and/or at least some of thecannula nosepiece and/or cannula can have about 30 to 70 durometerand/or about 50 durometer (Shore A).

In exemplary embodiments, cannula nosepiece 2002 can include threelumens in a “tornado” 2515 design that can allow sufficient rigidity forthe nasal nares, yet allows the nares to be partially compressible, forexample, because the dividing lines for the oxygen lumen 2008 andtriggering lumens 2004 can be offset (e.g., not aligned through thecenter of the NO delivery lumen 2003). This compressibility can allowfor the nasal prong to be more flexible and comfortable than othertri-lumen cannula prong designs.

In exemplary embodiments, the tornado can also encapsulate the smallerNO lumen 2004, the nasal nares can be designed to ensure optimal and/ora desired insertion distance, and/or to increase comfort the nasalcannula can be tapered from base to end and/or can be arcuate (e.g.,inwards towards the nasal openings). In exemplary embodiments, thisoptimal and/or desired insertion distance can be about 0.1 inches toabout 0.6 inches and/or about 0.40 inches.

In exemplary embodiments, the outlet geometry of the oxygen lumen (e.g.,at the cannula nosepiece) can be designed to reduce auditory frequencynoise (e.g., about 20 hz to 15 khz) by, for example, tapering of theoutlet of the oxygen lumen. Further, noise reduction can also beachieved by modification of the durometer of the oxygen carrying lumento prevent auditory range oscillation and noise due to oxygen flowand/or by selecting a geometry of the oxygen lumen that does notgenerate noise (e.g., vibration, resonance, etc.).

Referring to FIGS. 26A-26C, cross-sectional views show various exemplaryconfigurations for nasal cannula nares. For example, FIG. 26Aillustratively depicts a “tornado” pattern. FIGS. 26B-26D illustrativelydepict additional configurations that can include at least some of thebenefits disclosed for the “tornado” configuration. For example, otherconfigurations can allow sufficient rigidity for the nasal nares and canallow the nares to be partially compressible and/or other configurationsthat can provide at least some of the above benefits disclosed arewithin the scope of this invention.

In exemplary embodiments, the outer diameter of the cannula nosepiecenares can be minimized to increase patient comfort. Taking into accountthis outer dimension, the dimensions of the various lumens (e.g.,trigger lumen, NO lumen, O2 lumen, etc.) can be selected to not only beoptimized (e.g., as discussed herein) but can also be limited in size toaccount for patient comfort. For example, although it may be beneficialfor optimization to have nares with a larger outer diameter (e.g., anouter diameter of about 0.25 inches or larger), the nares of the cannulamay have an outer diameter of less than and/or about 0.2 inches forpatient comfort.

By way of example, taking into account patient comfort as well as atleast some and/or all of the metrics for optimization disclosed herein,a tri-lumen cannula (e.g., with a length of about 7 feet) can havetubing with an NO lumen having an ID of about 0.069 inches, a triggerlumen having an ID of about 0.089 inches, and an O2 lumen having an IDof about 0.089 inches with at least some of the lumens reducing at thecannula nosepiece (e.g., having a backplane length of about 0.59 inches)and/or reducing (e.g., reducing again) at the nares (e.g., having alength of about 0.47 inches) of the cannula nosepiece. For example, atthe cannula nosepiece the NO lumen can be reduced to an ID of about0.049 inches, the trigger lumen can have an ID of about 0.089 inches,and/or the O2 lumen can have an ID of about 0.089 inches. Stillfollowing the above example, at the nares of cannula nosepiece the NOlumen can be reduced to an ID of about 0.038 inches, the trigger lumencan be reduced to an ID of about 0.079 inches, and/or the O2 lumen canbe reduced to an ID of about 0.079 inches. Further, prior to the reducerand/or connection piece the NO lumen can have an ID of about 0.069inches, the trigger lumen can have an ID of about 0.089 inches, and theO2 lumen can have an ID of about 0.132 inches.

By way of example, taking into account patient comfort as well as atleast some and/or all of the metrics for optimization disclosed herein,a tri-lumen cannula (e.g., with a length of about 3 feet) can havetubing with an NO lumen having an ID of about 0.064 inches, a triggerlumen having an ID of about 0.084 inches, and an O2 lumen having an IDof about 0.084 inches with at least some of the lumens reducing at thecannula nosepiece (e.g., having a backplane length of about 0.59 inches)and/or reducing (e.g., reducing again) at the nares (e.g., having alength of about 0.47 inches) of the cannula nosepiece. For example, atthe cannula nosepiece the NO lumen can be reduced to an ID of about0.044 inches, the trigger lumen can have an ID of about 0.084 inches,and/or the O2 lumen can have an ID of about 0.084 inches. Stillfollowing the above example, at the nares of cannula nosepiece the NOlumen can be reduced to an ID of about 0.036 inches, the trigger lumencan be reduced to an ID of about 0.074 inches, and/or the O2 lumen canbe reduced to an ID of about 0.074 inches. Further, prior to the reducerand/or connection piece the NO lumen can have an ID of about 0.064inches, the trigger lumen can have an ID of about 0.084 inches, and theO2 lumen can have an ID of about 0.127 inches.

By way of example, taking into account patient comfort as well as atleast some and/or all of the metrics for optimization disclosed herein,a tri-lumen cannula (e.g., with a length of about 15 feet) can havetubing with an NO lumen having an ID of about 0.074 inches, a triggerlumen having an ID of about 0.094 inches, and an O2 lumen having an IDof about 0.094 inches with at least some of the lumens reducing at thecannula nosepiece (e.g., having a backplane length of about 0.59 inches)and/or reducing (e.g., reducing again) at the nares (e.g., having alength of about 0.47 inches) of the cannula nosepiece. For example, atthe cannula nosepiece the NO lumen can be reduced to an ID of about0.054 inches, the trigger lumen can have an ID of about 0.094 inches,and/or the O2 lumen can have an ID of about 0.094 inches. Stillfollowing the above example, at the nares of cannula nosepiece the NOlumen can be reduced to an ID of about 0.04 inches, the trigger lumencan be reduced to an ID of about 0.084 inches, and/or the O2 lumen canbe reduced to an ID of about 0.084 inches. Further, prior to the reducerand/or connection piece the NO lumen can have an ID of about 0.074inches, the trigger lumen can have an ID of about 0.094 inches, and theO2 lumen can have an ID of about 0.137 inches.

By way of example, taking into account patient comfort as well as atleast some and/or all of the metrics for optimization disclosed herein,a quad-lumen cannula (e.g., with a length of about 7 feet) can havetubing with at least one NO lumen having an ID of about 0.069 inches, atleast one trigger lumen having an ID of about 0.089 inches, and an O2lumen having an ID of about 0.089 inches with at least some of thelumens reducing at the cannula nosepiece (e.g., having a backplanelength of about 0.59 inches) and/or reducing (e.g., reducing again) atthe nares (e.g., having a length of about 0.47 inches) of the cannulanosepiece. For example, at the cannula nosepiece the NO lumen(s) can bereduced to an ID of about 0.049 inches, the trigger lumen(s) can have anID of about 0.089 inches, and/or the O2 lumen can have an ID of about0.089 inches. Still following the above example, at the nares of cannulanosepiece the NO lumen(s) can be reduced to an ID of about 0.038 inches,the trigger lumen(s) can be reduced to an ID of about 0.079 inches,and/or the O2 lumen can be reduced to an ID of about 0.079 inches.Further, prior to the reducer and/or connection piece the NO lumen(s)can have an ID of about 0.069 inches, the trigger lumen(s) can have anID of about 0.089 inches, and the O2 lumen can have an ID of about 0.132inches.

By way of example, taking into account patient comfort as well as atleast some and/or all of the metrics for optimization disclosed herein,a quad-lumen cannula (e.g., with a length of about 3 feet) can havetubing with at least one NO lumen having an ID of about 0.064 inches, atleast one trigger lumen having an ID of about 0.084 inches, and an O2lumen having an ID of about 0.084 inches with at least some of thelumens reducing at the cannula nosepiece (e.g., having a backplanelength of about 0.59 inches) and/or reducing (e.g., reducing again) atthe nares (e.g., having a length of about 0.47 inches) of the cannulanosepiece. For example, at the cannula nosepiece the NO lumen(s) can bereduced to an ID of about 0.044 inches, the trigger lumen(s) can have anID of about 0.084 inches, and/or the O2 lumen can have an ID of about0.084 inches. Still following the above example, at the nares of cannulanosepiece the NO lumen(s) can be reduced to an ID of about 0.036 inches,the trigger lumen(s) can be reduced to an ID of about 0.074 inches,and/or the O2 lumen can be reduced to an ID of about 0.074 inches.Further, prior to the reducer and/or connection piece the NO lumen(s)can have an ID of about 0.064 inches, the trigger lumen(s) can have anID of about 0.084 inches, and the O2 lumen can have an ID of about 0.127inches.

By way of example, taking into account patient comfort as well as atleast some and/or all of the metrics for optimization disclosed herein,a quad-lumen cannula (e.g., with a length of about 15 feet) can havetubing with at least one NO lumen having an ID of about 0.074 inches, atleast one trigger lumen having an ID of about 0.094 inches, and an O2lumen having an ID of about 0.094 inches with at least some of thelumens reducing at the cannula nosepiece (e.g., having a backplanelength of about 0.59 inches) and/or reducing (e.g., reducing again) atthe nares (e.g., having a length of about 0.47 inches) of the cannulanosepiece. For example, at the cannula nosepiece the NO lumen(s) can bereduced to an ID of about 0.054 inches, the trigger lumen(s) can have anID of about 0.094 inches, and/or the O2 lumen can have an ID of about0.094 inches. Still following the above example, at the nares of cannulanosepiece the NO lumen(s) can be reduced to an ID of about 0.04 inches,the trigger lumen(s) can be reduced to an ID of about 0.084 inches,and/or the O2 lumen can be reduced to an ID of about 0.084 inches.Further, prior to the reducer and/or connection piece the NO lumen(s)can have an ID of about 0.074 inches, the trigger lumen(s) can have anID of about 0.094 inches, and the O2 lumen can have an ID of about 0.137inches.

By way of example, taking into account patient comfort as well as atleast some and/or all of the metrics for optimization disclosed herein,a dual-lumen cannula (e.g., with a length of about 7 feet) can havetubing with a combined NO/trigger lumen having an ID of about 0.07inches and an O2 lumen having an ID of about 0.089 inches with at leastsome of the lumens reducing at cannula nosepiece (e.g., having abackplane length of about 0.59 inches) and/or reducing (e.g., reducingagain) at the nares (e.g., having a length of about 0.47 inches) of thecannula nosepiece. For example, at the cannula nosepiece the combinedNO/trigger lumen can be reduced to an ID of about 0.05 inches and/or theO2 lumen can have an ID of about 0.089 inches. Still following the aboveexample, at the nares of cannula nosepiece the combined NO/trigger lumencan be reduced to an ID of about 0.04 inches and/or the O2 lumen can bereduced to an ID of about 0.079 inches. Each of these dimensions for thecombined NO/trigger lumen may be increased slightly (e.g., by a fewthousands), for example, to reduce trigger signal attenuation. Further,prior to the reducer and/or connection piece the combined NO/triggerlumen can have an ID of about 0.07 inches, and the O2 lumen can have anID of about 0.132 inches.

By way of example, taking into account patient comfort as well as atleast some and/or all of the metrics for optimization disclosed herein,a dual-lumen cannula (e.g., with a length of about 3 feet) can havetubing with a combined NO/trigger lumen having an ID of about 0.064inches and an O2 lumen having an ID of about 0.084 inches with at leastsome of the lumens reducing at the cannula nosepiece (e.g., having abackplane length of about 0.59 inches) and/or reducing (e.g., reducingagain) at the nares (e.g., having a length of about 0.47 inches) of thecannula nosepiece. For example, at the cannula nosepiece the combinedNO/trigger lumen can be reduced to an ID of about 0.044 inches and/orthe O2 lumen can have an ID of about 0.0.084 inches. Still following theabove example, at the nares of cannula nosepiece the combined NO/triggerlumen can be reduced to an ID of about 0.036 inches and/or the O2 lumencan be reduced to an ID of about 0.074 inches. Each of these dimensionsfor the combined NO/trigger lumen may be increased slightly (e.g., by afew thousands), for example, to reduce trigger signal attenuation.Further, prior to the reducer and/or connection piece the combinedNO/trigger lumen can have an ID of about 0.064 inches, and the O2 lumencan have an ID of about 0.127 inches.

By way of example, taking into account patient comfort as well as atleast some and/or all of the metrics for optimization disclosed herein,a dual-lumen cannula (e.g., with a length of about 15 feet) can havetubing with a combined NO/trigger lumen having an ID of about 0.074inches and an O2 lumen having an ID of about 0.094 inches with at leastsome of the lumens reducing at cannula nosepiece (e.g., having abackplane length of about 0.59 inches) and/or reducing (e.g., reducingagain) at the nares (e.g., having a length of about 0.47 inches) of thecannula nosepiece. For example, at the cannula nosepiece the combinedNO/trigger lumen can be reduced to an ID of about 0.054 inches and/orthe O2 lumen can have an ID of about 0.094 inches. Still following theabove example, at the nares of cannula nosepiece the combined NO/triggerlumen can be reduced to an ID of about 0.040 inches and/or the O2 lumencan be reduced to an ID of about 0.084 inches. Each of these dimensionsfor the combined NO/trigger lumen may be increased slightly (e.g., by afew thousandths of an inch), for example, to reduce trigger signalattenuation. Further, prior to the reducer and/or connection piece thecombined NO/trigger lumen can have an ID of about 0.074 inches, and theO2 lumen can have an ID of about 0.137 inches.

Trampoline

In exemplary embodiments, cannula nosepiece 2002 can include a flexiblesupport bridge or “trampoline” 2517 that can cushion the nasal septum.Flexible support bridge 2517 can provide increased patient comfort by,for example, increasing the surface area of contact between the cannulaand the nasal septum and/or patient comfort can be increased because theprong bridge can be designed to deflect away from the nasal septum.

In exemplary embodiments, flexible support bridge 2517 can be an element(e.g., free floating element) that may be supported on both ends by theprongs of the nasal cannula. Rather than having a patient nose (e.g.,nasal septum) rest on a central bridge member 2518 commonly found innasal cannulas (e.g., that separates the nares of a nasal cannula; ahard plastic connection, sometimes curved, between the nares of a nasalcannula; etc.) flexible support bridge 2517 can be an element (e.g.,additional to central bridge 2518, traversing at least some of centralbridge 2518, traversing from one nare to another nare, etc.) contactingthe patient's septum thereby providing at least increased comfort to thepatient. In exemplary embodiments, flexible support bridge 2517 can“give” and/or “bend” towards central bridge member 2518 when the cannulais worn. The “give” and/or “bending” of flexible support bridge 2517 cansmooth transient forces on the nasal septum due to patient movement orcannula movement. The “give” and/or “bending” can also increase surfacearea of contact with the nasal septum, which in turn can reduce theforce on the nasal septum at any one point thereby improving comfort(e.g., as comfort may be adversely affected by increasing point load onthe nasal septum).

In exemplary embodiments, flexible support bridge 2517 can restrict thedepth of insertion of the nasal nares, for example, as mentioned above,to an optimal and/or desired insertion distance of about 0.1 inches toabout 0.6 inches and/or about 0.40 inches. By way of example, thisdistance can be shorter than the nasal nares length extending fromcentral bridge 2518.

In exemplary embodiments, the nasal cannula nosepiece can include a tab2519 between the nares (e.g., extending from central bridge 2518) thatcan allow the nasal cannula connection piece to sit properly on theupper lip. Tab 2519 can provide an additional measure of patient comfortby, for example, orienting the nares so the nares point inwards towardsthe nostril openings and/or can distribute force on the upper lip over alarger surface area thereby improving patient comfort.

Referring to FIGS. 20 and 27, in exemplary embodiments, the nasalcannula can include a keying member 2010, described in further detailbelow. In exemplary embodiments, keying member 2010 can be a bolo and/orcan be part of a bolo that can be included that can be used to adjustthe length of the cannula section proximal to the nosepiece, forexample, to increase patient comfort by ensuring the cannula fits aroundthe head of the wearer.

In exemplary embodiments, the nasal cannula can further include ear padsthat can, for example, slide over and/or be built into the cannulatubing at the point where the cannula tubing wraps the ears to improvecomfort and/or the ear pads can be foam tube extrusions which may haveaxial slits so they can slide over the cannula tubing.

Although this exemplary nasal cannula may be described as having certaincomponents, any and all of these components may be optional, may beeliminated, and/or can be combined and/or further separated.Furthermore, the nasal cannula may have any of the other components ormaterials otherwise described herein.

Cannula Keying

During the purging and/or washout procedure that can be used to clearthe nasal cannula of air and other gases prior to NO delivery, air/gasescan be purged by flowing NO-containing gas through the nasal cannula.However, due to the reaction of NO and the oxygen in the air, thiswashout procedure can produce NO2. Accordingly, it can be important thatthe patient not be wearing the nasal cannula during the purging and/orwashout procedure, for example, so that the NO2 cannot be administeredto the patient.

Referring back to FIG. 20, one or more embodiments of the presentinvention can provide a keying element 2010 on the nasal cannula. Such akeying element may be affixed close to the nares of the nasal cannula,such as within 5-25 inches of the nares of the cannula. One or moreexemplary embodiment of such a keying element can be seen referring toelement 2010 as shown in FIG. 20. The keying element can be provided asa bolo that can sit on a patient's chest and/or neck when the cannula isworn by the patient.

Referring to FIG. 28, keying element 2010 may need to be plugged intothe NO delivery device 2803 with a key slot or keyhole 2804 and/or thismay need to be done during the washout procedure. Due to the proximityof the keying device and the nares, the nares of the nasal cannulacannot be in the nares of the patient's nose when the keying element isplugged into the NO delivery device.

In one or more exemplary implementations of a NO delivery device with akeyhole and a nasal cannula with a keying element, the NO deliverydevice can perform the following functions:

-   -   a. The NO delivery device can prompt the patient to remove the        cannula and insert the keying element contained on the cannula        into a keyhole in the NO delivery device.    -   b. The keyhole can detect the presence of the key in the        keyhole. Exemplary methods for detecting the presence of the key        include, but are not limited to, electronic detection (e.g.        light beam detector, actuated switch, IR detection, magnetic        detection, etc.) or mechanical detection (e.g. microswitch)    -   c. The NO delivery device can ensure that the key is in the        keyhole before performing the washout procedure and can be        programmed to not perform the maneuver if the key is not in the        keyhole.    -   d. The NO delivery device can then perform the washout procedure        and inform the user of the completion of the procedure.    -   e. The NO delivery device can allow the user the remove the key        from the keyhole for initiation of NO therapy.

In exemplary embodiments, the keying element and/or key slot can be usedto ensure that the patient is not wearing the nasal cannula during thepurging and/or washout procedure. In exemplary embodiments, the keyingelement and/or key slot can be used to ensure authenticity of at leastthe cannula, expiration of at least the cannula. For example, the keyingelement and/or key slot can be used to limit the number of cannula usesand /or not allow patients to re-use the cannula. For another example,in the event of a need to ensure patients not use the cannula, thekeying element and/or key slot can be used prevent users from usingdefected cannula.

It will be understood that any of the above teachings (e.g., trampoline,tab, paratube, connection piece, oxygen connection piece, reducer,keying member, keying, bolo, cannula constructs, nosepiece constructs,etc.) can be combined with any of the other pneumatic configurations,cannula configurations, and/or teachings and/or embodiments describedherein. For example, the above teachings (e.g., trampoline, tab,paratube, connection piece, oxygen connection piece, reducer, keyingmember, keying, bolo, cannula constructs, nosepiece constructs, etc.)can be used with mono-lumen cannulas, dual-lumen cannulas, tri-lumencannulas, quad-lumen cannulas, and/or any other teachings and/orembodiments described herein.

EXAMPLES

Referring to FIGS. 29-30, an example of retrograde flow duringinspiratory breath along with pulsed delivery is shown at FIG. 29 and anexample of retrograde flow during both inspiratory and expiratory breathis shown at FIG. 30.

Referring to FIGS. 31 and 32A, 32B, and 32C, the retrograde flow forvarious nasal cannula configurations was tested. Typical nasal cannulasthat deliver to both nares result in significant retrograde flow asshown in Test 1 of FIG. 31. The nasal cannula configuration of Test 1 isshown in FIG. 32A. For Test 2, the interconnect between the two nareswas occluded to increase the distance between the nares to approximately19 inches in the hopes that would eliminate the retrograde flow. Thenasal cannula configuration of Test 2 is shown in FIG. 32B. As shown inTest 2 of FIG. 31, while the total volume of retrograde flow could bereduced, it was not eliminated. Further occluding the pathway with a 7foot distance between the nares, as shown in FIG. 32C, had minimalfurther impact, as shown in Test 3 of FIG. 31. Surprisingly, it wasfound that the only way tested that completely eliminated the retrogradeflow was when separate circuits were used for the NO delivery to each ofthe nares (i.e. a dual channel delivery system).

The document attached to U.S. Provisional Application No. 61/856,367,filed Jul. 19, 2013 as Appendix 1, titled “Exploratory Evaluation ofNitrogen Dioxide Formation in Candidate Nitric Oxide Delivery Lumena,”examined the concentration of NO2 anticipated to be present in the iNOdelivery lumen of tri-lumen cannulas made of various materials. Appendix1 attached to U.S. Provisional Application No. 61/856,367, filed Jul.19, 2013 is incorporated by reference herein in its entirety; to theextent it is not inconsistent with the present invention. Theexperimental technique involved the flowing of 2440 ppm nitric oxide(balance nitrogen) gas through multiple tubes (of three material types)arranged in parallel such that proximal (based on the circuit withoutthe tubes) and distal readings of the effluent NO2 content could betaken using a CAPs NO2 bench. Parallel tubes were used to improve thesignal-to-noise ratio (i.e. to magnify the NO2 signal strength) of thedata and a final mathematical calculation of individual tube NO2 changewas obtained. The flow of nitric oxide through the parallel tubing bankswas set to equate to a residence time of 7.57 min/tube (e.g., based on a50 kg patient with dosing set to 0.003 mg/kg*hr with an iNO deliverytube of 84 inches length and 0.076 inches inner diameter). The “pertube” expected NO2 rise for the three material types tested is shown inbelow.

Per Tube Delivered NO2 Levels Tubing Material Per tube NO2 levelPolyvinyl Chloride 12.7 ppm Silicone 10.9 ppm Polyurethane  6.8 ppm

Methods of Treatment

The invention herein can reduce retrograde flow, ensure accurate dosedelivery, and/or minimize NO2 formation and used in conjunction with adelivery device can be used for the treatment and or prevention ofPulmonary hypertension secondary to COPD and/or Pulmonary hypertensionas PAH and/or Pulmonary hypertension secondary to IPF and/or Pulmonaryhypertension secondary to sarcoidosis.

For safe and effective use the disclosed cannula may be used with thedisclosed delivery device, and the like, and/or nitric oxide. Oneskilled in the art will appreciate that using a cannula other than thedisclosed cannula along with the disclosed delivery device, and thelike, and/or nitric oxide may increase safety risks and/or reduce and/oreliminate effective use. Accordingly, the cannula of present inventionmay be necessary for delivering nitric oxide for PAH, IPF, and/or COPD.

Any of the nasal cannulas described herein can be used in nitric oxidetherapy to treat appropriate diseases. For example, the cannulas can befor pulsed NO therapy to treat chronic obstructive pulmonary disease(COPD) or pulmonary arterial hypertension (PAH). For these diseases, thedelivery of the appropriate dose amounts and appropriate dose timing maybe very important. For COPD, the NO may need to be pulsed early ininspiration, such as the first half of inspiration. If NO is, forexample, not delivered in the right amount or at the right time,reversal of hypoxic vasoconstriction can occur, which could worsen thepatient's condition. Furthermore, the dose amount can be very importantfor PAH because sudden discontinuation of therapy can lead to seriousevents such as rebound hypertension. Thus, significant dilution of theNO dose should be minimized for these diseases. Any of the cannulamaterials, configurations or methods described herein can be used tominimize dilution of the NO dose during NO therapy.

In exemplary embodiments, lumens (e.g., tubes) of the cannula can carrybackwards towards the patient and/or can be affixed to each other so asto produce a substantially singular element umbilical between thecannula nosepiece and the device, which can provide a cross-section. Itwill be understood that when describing a plurality of lumens (e.g., twolumens, three lumens, four lumens, etc.) all of the lumens can beincluded in a single cannula.

In exemplary embodiments, elements of the cannula can be manufacturedusing any of the techniques disclosed herein and/or using techniquesknown in the art. For example, cannula lumens (e.g., tubes), nosepiece,key member, connectors, reducers, any combination and/or furtherseparation thereof, and/or any element of cannulas described herein canbe manufacturing using extrusion techniques, molding techniques, and/orusing any other manufacturing technique.

It will be understood that the each lumen the nasal cannula and/orcollective nasal cannula lumen cross-section can be any shape such as,but not limited to, to circular, parabolic, ellipsoidal, square,rectangular, triangular, and/or any other cross-section and/or or anyother regular or irregular shape to minimize dose dilution. For ease, attimes the geometry and/or cross-section is described as circular,parabolic, and/or ellipsoidal and/or the cross-section is described as adiameter, inner diameter, or the like. This is merely for ease and is inno way meant to be a limitation. When one or more cross-sectional areasare not circular, then the ratio of inner diameters can be the squareroot of the ratio of the surface areas of the two lumina sections.

It will be understood that any of the above can be used for pulsedand/or non-pulsed delivery of a therapeutic gas (e.g., NO). For example,any of the above embodiments referencing pulsed delivery of atherapeutic gas, when applicable, can be used with non-pulsed deliveryof a therapeutic gas, and vice versus. For ease, at times, reference maybe made to pulsed or non-pulsed. This is merely for ease and is in noway meant to be a limitation.

Reference throughout this specification to “one embodiment,” “certainembodiments,” “one or more embodiments,” “exemplary embodiment,”“exemplary embodiments,” and/or “an embodiment” means that a particularfeature, structure, material, or characteristic described in connectionwith the embodiment is included in at least one embodiment of theinvention. Thus, the appearances of the phrases such as “in one or moreembodiments,” “in certain embodiments,” “in one embodiment,” “exemplaryembodiment,” “exemplary embodiments,” and/or “in an embodiment” invarious places throughout this specification are not necessarilyreferring to the same embodiment of the invention. Furthermore, theparticular features, structures, materials, or characteristics can becombined in any suitable manner in one or more embodiments.

It will be understood that any of the steps described can be rearranged,separated, and/or combined without deviated from the scope of theinvention. For ease, steps are, at times, presented sequentially. Thisis merely for ease and is in no way meant to be a limitation.

Further, it will be understood that any of the elements and/orembodiments of the invention described can be rearranged, separated,and/or combined without deviated from the scope of the invention. Forease, various elements are described, at times, separately. This ismerely for ease and is in no way meant to be a limitation.

Although the disclosure herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It will be apparent to those skilled in the art thatvarious modifications and variations can be made to the method andapparatus of the present invention without departing from the spirit andscope of the invention. Thus, it is intended that the present inventioninclude modifications and variations that are within the scope of theappended claims and their equivalents.

What is claimed is:
 1. A nasal cannula for therapeutic gas delivered toa patient in need thereof, comprising: a first lumen, a second lumen,and a third lumen: the first lumen being a first therapeutic gas lumenfor delivering a first therapeutic gas to a patient in need thereof, thesecond lumen being a triggering lumen, and the third lumen being asecond therapeutic gas lumen for delivering a second therapeutic gas tothe patient; and a cannula nosepiece allowing separate flow paths to thepatient for at least one of (i) the first therapeutic gas lumen, (ii)the triggering lumen, and (iii) the second therapeutic gas lumen.
 2. Thenasal cannula of claim 1, wherein the nasal cannula (i) reduces dilutionof one or more of the first and second therapeutic gases delivered tothe patient or (ii) is configured to be placed in fluid communicationwith at least one system to deliver one or more of the first and secondtherapeutic gases to the patient, or both.
 3. The nasal cannula of claim1, wherein the nasal cannula at least one of inhibits mixing of nitricoxide and oxygen and reduces delivery of nitrogen dioxide to thepatient.
 4. The nasal cannula of claim 1, wherein the nasal cannuladelivers one or more of the first and second therapeutic gases to thepatient for treatment of pulmonary hypertension.
 5. The nasal cannula ofclaim 1, wherein the nasal cannula delivers one or more of the first andsecond therapeutic gases to the patient for treatment of at least one ofpulmonary hypertension secondary to chronic obstructive pulmonarydisease (COPD), pulmonary hypertension as pulmonary arterialhypertension (PAH), pulmonary hypertension secondary to idiopathicpulmonary fibrosis (IPF), and pulmonary hypertension secondary tosarcoidosis.
 6. The nasal cannula of claim 1, wherein the firsttherapeutic gas is nitric oxide and the second therapeutic gas isoxygen, and wherein the first therapeutic gas lumen for deliveringnitric oxide is smaller than the second therapeutic gas lumen fordelivering oxygen and the triggering lumen.
 7. The nasal cannula ofclaim 1, wherein the first therapeutic gas is nitric oxide and the firsttherapeutic gas lumen for delivering nitric oxide is about six feet toabout eight feet in length having an inner diameter of about 0.01 inchesto about 0.10 inches.
 8. The nasal cannula of claim 1, wherein the firsttherapeutic gas is nitric oxide and the cannula nosepiece comprises anitric oxide flow path having an inner diameter that is smaller than aninner diameter of the first therapeutic gas lumen.
 9. The nasal cannulaof claim 1, wherein the first therapeutic gas is nitric oxide and thecannula nosepiece comprises a nitric oxide flow path having a volumethat is less than about 10% of a minimum pulse volume of the pulse ofnitric oxide.
 10. The nasal cannula of claim 1, wherein the cannulacomprises a wall material having a low oxygen transmission rate that isbetween$0.001\frac{\left( {cm}^{3} \right)({mil})}{\left( {24\mspace{14mu} {hrs}} \right)\left( {100\mspace{14mu} {in}^{2}} \right)({ATM})}\mspace{14mu} {and}\mspace{14mu} 10{\frac{\left( {cm}^{3} \right)({mil})}{\left( {24\mspace{14mu} {hrs}} \right)\left( {100\mspace{14mu} {in}^{2}} \right)({ATM})}.}$11. The nasal cannula of claim 1, wherein the cannula is furthercomprising a fourth lumen: the fourth lumen being another firsttherapeutic gas lumen for delivering the first therapeutic gas to thepatient; and wherein the first lumen delivers the first therapeutic gasto one nostril of the patient and the fourth lumen delivers the firsttherapeutic gas to another nostril of the patient.
 12. The nasal cannulaof claim 1, further comprising one or more of: (i) at least one checkvalve in fluid communication with the first therapeutic gas lumen, (ii)a cannula key, (iii) a scavenging material, and (iv) a flexible supportbridge.
 13. A nasal cannula for therapeutic gas delivered to a patientin need thereof, comprising: a first lumen, a second lumen, and a thirdlumen: the first lumen being a first therapeutic gas lumen fordelivering a first therapeutic gas to a patient, the second lumen beinga triggering lumen for triggering release of a pulse of the firsttherapeutic gas, and the third lumen being a second therapeutic gaslumen for delivering a second therapeutic gas to the patient; the firsttherapeutic gas lumen, the triggering lumen, and the second therapeuticgas lumen aggregating at a cannula nosepiece, the cannula nosepieceallowing separate flow paths to the patient for each of the firsttherapeutic gas lumen, the triggering lumen, and the second therapeuticgas lumen; and the first therapeutic gas lumen having an inner diameterthat is one or more of (i) smaller than an inner diameter of the secondtherapeutic gas lumen and an inner diameter of the triggering lumen and(ii) larger than an inner diameter of the flow path for the firsttherapeutic gas lumen at the cannula nosepiece.
 14. The nasal cannula ofclaim 13, wherein the nasal cannula (i) reduces dilution of one or moreof the first and second therapeutic gases delivered to the patient or(ii) is configured to be placed in fluid communication with at least onesystem to deliver one or more of the first and second therapeutic gasesto the patient, or both.
 15. The nasal cannula of claim 13, wherein thenasal cannula at least one of inhibits mixing of nitric oxide and oxygenand reduces delivery of nitrogen dioxide to the patient.
 16. The nasalcannula of claim 13, wherein the nasal cannula delivers one or more ofthe first and second therapeutic gases to the patient for treatment ofpulmonary hypertension.
 17. The nasal cannula of claim 13, wherein thenasal cannula delivers one or more of the first and second therapeuticgases to the patient for treatment of at least one of pulmonaryhypertension secondary to chronic obstructive pulmonary disease (COPD),pulmonary hypertension as pulmonary arterial hypertension (PAH),pulmonary hypertension secondary to idiopathic pulmonary fibrosis (IPF),and pulmonary hypertension secondary to sarcoidosis.
 18. The nasalcannula of claim 13, wherein the first therapeutic gas is nitric oxideand the first therapeutic gas lumen for delivering nitric oxide is aboutsix feet to about eight feet in length having an inner diameter of about0.01 inches to about 0.10 inches.
 19. The nasal cannula of claim 13,wherein the first therapeutic gas is nitric oxide and the cannulanosepiece comprises a nitric oxide flow path having a volume that isless than about 10% of a minimum pulse volume of the pulse of nitricoxide.
 20. The nasal cannula of claim 13, wherein the cannula comprisesa wall material having a low oxygen transmission rate that is between$0.001\frac{\left( {cm}^{3} \right)({mil})}{\left( {24\mspace{14mu} {hrs}} \right)\left( {100\mspace{14mu} {in}^{2}} \right)({ATM})}\mspace{14mu} {and}\mspace{14mu} 10{\frac{\left( {cm}^{3} \right)({mil})}{\left( {24\mspace{14mu} {hrs}} \right)\left( {100\mspace{14mu} {in}^{2}} \right)({ATM})}.}$